CN101679371A - Substituted pyrimidines as adenosine receptor antagonists - Google Patents
Substituted pyrimidines as adenosine receptor antagonists Download PDFInfo
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- CN101679371A CN101679371A CN200780050872A CN200780050872A CN101679371A CN 101679371 A CN101679371 A CN 101679371A CN 200780050872 A CN200780050872 A CN 200780050872A CN 200780050872 A CN200780050872 A CN 200780050872A CN 101679371 A CN101679371 A CN 101679371A
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Abstract
Compounds of formula (I) including pharmaceutically acceptable salts, esters, solvates and stereoisomers thereof, R<1>, R<2> and R<3> are as defined herein. Pharmaceutical compositions containing a compound of structure (I), as well as methods relating to the use thereof, are also disclosed.
Description
The cross reference of related application
The application requires in the interests of the U.S. Provisional Application 60/868,517 of submission on December 4th, 2006, and this application is all incorporated herein by reference with it.
Background technology
Technical field
The present invention relates to novel adenosine receptor antagonists, particularly relate to A
2AThe antagonist of Adenosine Receptors hypotype, and described compound is easy to the disease improved by the antagonism Adenosine Receptors and the purposes in the illness in treatment, and relate to the pharmaceutical composition that comprises described compound.Known to using A
2AThe central nervous system disorders that adenosine receptor antagonists improves comprises for example Parkinson's disease, Huntington Chorea, restless leg syndrome and dyskinesia.
Description of Related Art
The effect of adenosine is subjected at least 4 kinds to be identified and to classify as A at present
1, A
2A, A
2BAnd A
3Acceptor and the specific cell membrane receptor that belongs to g protein coupled receptor family are regulated.A
1And A
3The cAMP level that acceptor is regulated cell by the decrement with the G protein binding suppresses adenylate cyclase thus.Under the contrast, A
2AAnd A
2BReceptors bind G albumen and activate adenylate cyclase and increase cAMP level in the cell.Regulate physiological function widely by these acceptor adenosines.
Therefore, in cardiovascular systems, A
1The activates relay heart tissue of acceptor is avoided ischemic and anoxybiotic influence.A
2AThe antagonistic action of acceptor also produces similar provide protection, strengthens A thus
1-acceptor-inductive antiadrenergic drug can react, and may also help to treat acute myocardial ischemia and supraventricular arrhythmia (Norton GR etc., Am J Physiol.1999; 276 (2 Pt 2): H341-9; Auchampach JA, Bolli R.Am J Physiol.1999; 276 (3 Pt 2): H1113-6).In addition, A
2BThe Adenosine Receptors hypotype (Feoktistov, I. etc., Pharmacol.Rev.1997,49,381-402) as if relevant with the growth of adjusting vascular smooth muscle with the control vascular tone.
In kidney, adenosine performance biphasic effect, induction of vascular diastole when high density and during at lower concentration induction of vascular shrink.Therefore, adenosine is may be by A
1Work in the pathogeny of the acute renal failure of some type that receptor antagonist improves (Costello-Boerrigter LC, etc., Med Clin NorthAm.2003Mar; 87 (2): 475-91; Gottlieb SS., Drugs.2001; 61 (10): 1387-93).
Adenosine is also relevant with immune physiopathology.It can pass through A
2BAnd/or A
3The human mast cell threshing that receptor-inducible has activated.Therefore, A
2BAnd/or A
3Antagonist prevents the mastocyte threshing, and therefore helps treatment, prevents or suppress by A
2BAnd/or A
3Receptor activation and mastocyte threshing inductive morbid state.These morbid states including, but not limited to asthma, reperfusion injury of cardiac muscle, anaphylaxis including, but not limited to rhinitis, urticaria, sclerderm sacroiliitis, other autoimmune disorder and inflammatory bowel disease.
In addition, in respiratory system, adenosine is induced bronchoconstriction, regulates bronchitis and promotes neutrocyte chemokine.Therefore, adenosine antagonist may help to treat asthma especially.
In stomach and intestine and metabolic system, A
2BThe Adenosine Receptors hypotype (Feoktistov, I. etc., Pharmacol.Rev.1997,49,381-402) as if relevant with the generation of adjusting liver glucose, adjusting intestines tensity and intestinal secretion.Therefore, A
2BAntagonist may also help to treat diabetes and obesity.
In central nervous system, adenosine is effective endogenous neuroregulator, and its presynaptic of regulating and control many neurotransmitters discharges and therefore relevant with motor function, sleep, anxiety, pain and psychomotor function.All Adenosine Receptors hypotypes all are present in the brain, A
1And A
2AHypotype distributes different.The former mainly is distributed in hippocampus and cortex, and the latter mainly is distributed in striatum.Adenosine A
2AAcceptor is regulated the release of GABA in the striatum, thereby may regulate medium-sized many sour jujubes function of neurons.
Therefore, A
2AReceptor antagonist has and helps treat neurodegeneration movement disorders such as Parkinson's disease and Huntington Chorea (Tuite P is etc., J.Expert Opin Investig Drugs.2003; 12:1335-52; Popoli P. etc., J Neurosci.2002; 22:1967-75), (Happe S is etc., Neuropsychobiology.2003 for dystonia such as restless leg syndrome; 48:82-6), and disease (the Jenner P.J Neurol.2000 that for example causes of dyskinesia by taking tranquilizer and Dopamine HCL medicine for a long time; 247Suppl2:II43-50).
In Parkinsonian treatment, A
2AAntagonist can be not only effective as monotherapy, and also effective when with the following drug regimen administration of L-DOPA and/or one or more.Described medicine is: dopamine agonist, Dopamine HCL decarboxylase inhibitor, catechol-O-methyltransferase inhibitor and oxidase inhibitor.
In addition, A
2AAntagonist may have treatment potentiality (Stone TW. etc., the Drug.Dev.Res.2001 as neuroprotective; 52:323-330) and be used for the treatment of somnopathy (Dunwiddie TV etc., Ann.Rev.Neurosci.2001; 24:31-55).
Have now found that some 4-aminopyridine derivative is A
2ANovel effective antagonist of Adenosine Receptors, therefore and can be used for the treatment of or prevent the disease that can be improved by the Adenosine Receptors antagonistic action.
Another object of the present invention provides the method for pharmaceutical composition that is used to prepare described compound, comprises the described compound of significant quantity; Described compound is used for the treatment of in preparation can be by the antagonistic action of Adenosine Receptors (particularly by A
2AThe antagonistic action of Adenosine Receptors) purposes in the medicine of the pathology patient's condition of Gai Shaning or disease; Treatment can be by the Adenosine Receptors antagonistic action, particularly by A
2AThe pathology patient's condition that the antagonistic action of Adenosine Receptors is improved or the method for disease, described method comprises the individuality of compound administration of the present invention in the needs treatment, and described compound and one or more following drug regimen administrations, wherein said medicine is: L-DOPA, dopamine agonist, Dopamine HCL decarboxylase inhibitor, catechol-O-methyltransferase inhibitor and oxidase inhibitor.
Summary of the invention
In brief, the present invention relates generally to adenosine receptor antagonists, and their preparation method and using method, and relates to the pharmaceutical composition that comprises them.More specifically, adenosine receptor antagonists of the present invention is the compound with following formula (I):
With and pharmacologically acceptable salts, ester, solvate and steric isomer, wherein R
1, R
2And R
3Be defined as follows.
Compound of the present invention generally can be used for the treatment of numerous disease or illness, and particularly treatment is benefited from and suppressed adenosine (A especially
2A) those of acceptor.Therefore, in another embodiment, announced the method that is used for the treatment of one or more diseases or illness, described disease or illness include but is not limited to ischemic, supraventricular arrhythmia, acute renal failure, reperfusion injury of cardiac muscle, autoimmune disorder, inflammatory bowel disease, asthma, diabetes, obesity, Parkinson's disease, Huntington Chorea, dystonia and dyskinesia.
Method of the present invention generally comprises usually form with pharmaceutical composition to one or more compounds of the present invention that this animal (be also referred to as " patient " herein, comprise the mankind) effective dosage that needs is arranged.Therefore, in yet another embodiment, announced the composition that includes one or more compounds of the present invention and pharmaceutically acceptable carrier and/or thinner.
After following detailed description part, these and other aspect of the present invention will be apparent.For this reason, list the document of some method of various detailed descriptions, compound and/or composition herein, and these documents are all incorporated herein by reference with it.
Detailed Description Of The Invention
As mentioned above, the present invention relates in general to the compound as adenosine receptor antagonists.Compound of the present invention has following structure (I):
And pharmacologically acceptable salts, ester, solvate and steric isomer, wherein:
R
1It is the heterocycle that is randomly replaced by one or more members that are selected from low alkyl group, lower alkoxy, halogen and cyano group;
R
2Be NR
4R
5Or heterocycle, wherein said heterocycle is by 0-4 R
4Group replaces;
R
3Be H, R
6, OR
6, COR
6, CONR
6R
7, COOR
6Or containing the heteroaryl of at least one nitrogen, wherein said heteroaryl is randomly by 0-4 R
4Replace;
R
4Be selected from when occurring at every turn low alkyl group, lower alkoxy, alkoxyalkyl, oxo, cyano group, halogen, hydroxyl ,-C (O)-alkyl, low-grade alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycle and Heterocyclylalkyl, wherein said low alkyl group, lower alkoxy, alkoxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycle and heterocycloalkyl randomly by one or more low alkyl groups, halogen, lower alkoxy, hydroxyl, cyano group, aryl and-C (O)-alkyl replaces;
R
5Be selected from hydrogen, low alkyl group, lower alkoxy and alkoxyalkyl when occurring at every turn;
R
6Be low alkyl group, aralkyl, heteroaryl or Heterocyclylalkyl, wherein said low alkyl group, aralkyl, heteroaryl and heterocycloalkyl are randomly replaced by one or more members that are selected from low alkyl group, lower alkoxy, hydroxyl, oxo, halogen, amino, alkylamino and dialkyl amido; And
R
7Be hydrogen or low alkyl group, wherein said low-grade alkyl group is randomly replaced by one or more members that are selected from alkoxyl group, hydroxyl, oxo, halogen, amino, alkylamino and dialkyl amido.
Others of the present invention are: a) comprise the pharmaceutical composition of the The compounds of this invention of pharmacy effective dose, b) compound of the present invention is used for the treatment of in preparation and is easy to by the antagonism Adenosine Receptors, especially by antagonism A
2APurposes in the medicine of the disease that Adenosine Receptors improves; And c) treatment is easy to by the antagonism Adenosine Receptors, particularly by antagonism A
2AThe method of the disease that Adenosine Receptors improves, described method comprise to the individual administration compound of the present invention that these needs are arranged.The present invention also comprises compound of the present invention and the medication combined individuality that delivers medicine to these needs: L-DOPA, dopamine agonist, Dopamine HCL decarboxylase inhibitor, catechol-O-methyltransferase inhibitor and oxidase inhibitor below one or more.
As used in this article, term lower alkyl comprises the optional alkyl group that contains 1-8 carbon atom that replace, straight or branched.Typical low alkyl group has 1-6 or 1-4 carbon atom.Substituent representative example in the described alkyl group is halogen, hydroxyl and amino.
The example of low-grade alkyl group comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl and the tertiary butyl, n-pentyl, 1-methyl butyl, 2-methyl butyl, isopentyl, 1-ethyl propyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, n-hexyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methyl amyl, 3-methyl amyl and isohexyl group.
What as used in this article, the term lower alkoxy comprised optional that replace, straight or branched contains 1-8, typically 1-6 and the oxy radical of the moieties of 1-4 carbon atom more typically separately.Substituent representative example on the described alkoxyl group is halogen, hydroxyl and amino.
The example of lower alkoxy groups comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, trifluoromethoxy, difluoro-methoxy, hydroxyl methoxyl group, 2-hydroxyl-oxethyl or 2-hydroxyl propoxy-.
As used in this article, the term lower alkylthio comprises and contains optional that replace, straight or branched 1-8, typically 1-6 and the group of the alkyl group of 1-4 carbon atom more typically.Representative substituting group on the described alkylthio group alkylthio is halogen, hydroxyl and amino.
The example of the optional lower alkylthio that replaces comprises methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, secondary butylthio, uncle's butylthio, trifluoromethylthio, difluoro methylthio group, hydroxyl methylthio group, 2-hydroxyl ethylmercapto group or 2-hydroxyl rosickyite base.
As used in this article, term " acyl group " be meant by formula alkyl-C (=O)-group of expression, wherein said alkyl group can be that replace or unsubstituted.
Unless otherwise indicated, as used in this article, the term cyclic group comprises carbocyclic ring and heterocyclic group.Described cyclic group can comprise one or more rings.Carbon ring group can be aromatic ring or alicyclic ring, for example group of naphthene base.Heterocyclic group also comprises the heterocyclic base group.
As used in this article, term aromaticity group typically comprises 5-to 14-unit aromatic ring system, for example can comprise heteroatomic 5-or the 6-unit ring of one or more O of being selected from, S and N.When no heteroatoms existed, this group was called as aromatic yl group, and when having a heteroatoms at least, then it is called as heteroaryl groups.Described aromaticity group can be monocycle or polycyclic, for example phenyl or naphthyl.When aromaticity group or aromaticity partly had 2 or a plurality of substituting group, these substituting groups can be identical or different.
As used in this article, the term aryl group typically comprises C
5-C
14Monocycle or polyaromatic group, for example phenyl, naphthyl, anthryl or phenanthryl.When aromatic yl group had 2 or a plurality of substituting group, these substituting groups can be identical or different.
As used in this article, the term heteroaryl groups typically comprises and contains at least one hetero-aromatic ring and contain at least one the heteroatomic 5-to 14-that is selected from O, S and N unit member ring systems.Heteroaryl groups can be monocycle or two or more condensed ring, and wherein at least one ring comprises heteroatoms.
The example of heteroaryl comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, furyl oxadiazole base oxazolyl isoxazolyl, imidazolyl, thiazolyl, thiadiazolyl group, thienyl, pyrryl, benzothiazolyl, indyl, indazolyl, purine radicals, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, quinolizinyl, the cinnolines base, triazolyl, the indolizine base, the indoline base, the isoindoline base, pseudoindoyl, imidazolidyl, pteridyl and pyrazolyl.When heteroaryl groups had 2 or a plurality of substituting group, described substituting group can be identical or different.
As used in this article, the term heterocyclic radical typically comprises and contains at least one heterocycle and comprise at least one the heteroatomic 5-to 14-that is selected from O, S and N unit member ring systems.Heterocyclic radical can be monocycle or two or more condensed ring, and wherein at least one ring includes heteroatoms.Heterocyclic radical can be an aromaticity, and it is a heteroaryl groups in the case, and perhaps it can be non-aromaticity.
Above provide the example of aromaticity heterocycle (being heteroaryl).Non-aromaticity heterocycle comprises piperidyl, piperazinyl, morpholinyl, pyrrolidyl, thio-morpholinyl, oxazolidinyl, imidazolidyl, thiazolidyl, azepan base (azepanyl), [1,4] the Diazesuberane base ([1,4] [1,4] oxygen azepine diazepanyl),
Base ([1,4] oxazepanyl) and sulphur azepine
Base (thiazepanyl).
As used in this article, the term cycloalkyl comprises saturated, the optional carbocylic radical that replaces, and unless otherwise indicated, group of naphthene base typically contains 3-7 carbon atom.Preferred substituents on the described group of naphthene base is selected from halogen atom, oh group, alkyl group and amino group.
Example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.Preferred cyclopropyl, cyclopentyl or cyclohexyl.When group of naphthene base had 2 or a plurality of substituting group, these substituting groups can be identical or different.
As used in this article, be present in some atoms in the universal architecture of the present invention, group, partly, chain or ring be " the optional replacement ".This means these atoms, group, partly, chain or ring can be unsubstituted, or on any position, replaced by one or more as 1,2,3 or 4 substituting group, be thus connected at unsubstituted atom, group, partly, chain or ring hydrogen atom by chemically acceptable atom, group, partly, chain or ring replace.When having two or more substituting group, each substituting group can be identical or different.
The substituting group of " the optional replacement " structure can be including, but not limited to one or more, typically 1-4 and 1-2 following substituting group more typically: alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, alkoxyl group, aryloxy, alkylthio, arylthio, cycloalkyl, aralkyl, amino, alkylamino, dialkyl amido, amide group (as CONH2, CONH alkyl and CONH dialkyl group and reverse NCOH or NCO alkyl), F, Cl, Br, I, CN, NO
2, NH
2, NHCH
3, NHCH2CH
3, N (CH
3)
2, N (CH
2CH
3)
2, SH, SCH
3, OH, OCH
3, OCF
3, CH
3And CF
3
As used in this article, the term halogen atom comprises chlorine, fluorine, bromine or iodine atom, typically is fluorine, chlorine or bromine atom, most preferably is chlorine or fluorine.When the term halo was used as prefix, it had same implication.
As used in this article, the term pharmacologically acceptable salts comprises the salt that forms with acceptable acid of pharmacy or alkali.The acceptable acid of pharmacy comprises mineral acid, for example hydrochloric acid, sulfuric acid, phosphoric acid, tetra-sodium, Hydrogen bromide, hydroiodic acid HI and nitric acid, and organic acid, for example citric acid, fumaric acid, toxilic acid, oxysuccinic acid, amygdalic acid, xitix, oxalic acid, succsinic acid, tartrate, phenylformic acid, acetate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid or tosic acid.The acceptable alkali of pharmacy comprises basic metal (as sodium or potassium) oxyhydroxide and alkaline-earth metal (as calcium or magnesium) oxyhydroxide and organic bases, for example alkylamine, aralkylamine and heterocyclic amine.
Other preferably salt according to the present invention is a quaternary ammonium compound, wherein negatively charged ion (X
-) Equivalent combines with the positive charge of N atom.X
-It can be the negatively charged ion of multiple mineral acid, for example chlorion, bromide anion, iodide ion, sulfate ion, nitrate ion, phosphate anion, or organic acid negatively charged ion, for example acetate ion, maleate ion, fumarate ion, citrate ion, oxalate denominationby, succinate ion, tartrate anion ion, malate ion, amygdalic acid radical ion, trifluoroacetic acid radical ion, methanesulfonate ion and tosic acid radical ion.X
-Preferably be selected from the negatively charged ion of chlorion, bromide anion, iodide ion, sulfate ion, nitrate ion, acetate ion, maleate ion, oxalate denominationby, succinate ion or trifluoroacetic acid radical ion.More preferably X
-Be chlorion, bromide anion, trifluoroacetic acid radical ion or methanesulfonate ion.
As used in this article, the N-oxide compound is to use suitable oxygenant to be formed by basic tertiary amine that exists in the molecule or imines.
In one embodiment of the invention, in the compound of formula (I), R
1The heterocycle that expression is randomly replaced by the one or more members that are selected from low alkyl group, lower alkoxy, halogen and cyano group.
According to one embodiment of the invention, R
1Represent such heteroaryl groups, this heteroaryl groups is selected from pyridyl, furyl, thienyl, thiazolyl, oxazole, pyrazolyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl He oxadiazole base group, and they are randomly replaced by the substituting group of one or more low alkyl groups that are selected from halogen, hydroxyl, amino, alkylamino, the lower alkoxy that randomly replaces and randomly replace.
In one embodiment of the invention, R
1Expression is selected from following heteroaryl groups:
In one embodiment of the invention, in the compound of formula (I), R
2Expression is randomly by 0-4 R
4The heterocycle that group replaces.
At wherein R of the present invention
2Be in embodiment of heterocyclic, R
2Expression randomly by one or more be selected from alkyl, alkoxyl group, alkoxyalkyl, benzyloxy, phenoxyalkyl, hydroxyl, hydroxyalkyl, halogen, amino, alkylamino, dialkyl amido, amide group ,-pyrrolidyl that the substituting group of C (O) O-alkyl and morpholinyl replaces.
At wherein R of the present invention
2Be in another embodiment of heterocyclic, R
2Expression randomly by one or more be selected from alkyl, alkoxyl group, alkoxyalkyl, benzyloxy, phenoxyalkyl, hydroxyl, hydroxyalkyl, halogen, amino, alkylamino, dialkyl amido, amide group ,-piperidyl that the substituting group of C (O) O-alkyl and morpholinyl replaces.
At wherein R of the present invention
2Be in another embodiment of heterocyclic, R
2Indyl or pseudoindoyl that expression is randomly replaced by one or more substituting groups that are selected from alkyl, alkoxyl group, alkoxyalkyl and cyano group.
At wherein R of the present invention
2Be in another embodiment of heterocyclic, R
2Monocycle or bicyclic lactone that expression is randomly replaced by one or more alkyl or cycloalkyl groups.
At wherein R of the present invention
2Be NR
4R
5Another embodiment in, R
2Expression N-alkoxy amino, anilino or the aminopyridine base that is randomly replaced by one or more substituting groups that are selected from alkoxyl group and halogen, lactam group, the tetrahydro pyridyl that is replaced by phenyl randomly, randomly by phenyl, the piperazinyl that benzyl or pyridyl replace, aziridinyl (azeridinyl), the morpholinyl that is replaced by one or more alkyl randomly, randomly by one or more alkoxyl groups that are selected from, hydroxyl, heterocyclic radical, the alkylamino that the substituting group of aryl and heteroaryl replaces, and randomly by one or more alkoxyl groups that are selected from, hydroxyl, heterocyclic radical, the dialkyl amido that the substituting group of aryl and heteroaryl replaces.
According to another embodiment of the present invention, in the compound of formula (I), R
2Expression contains the heterocycle of at least one nitrogen-atoms, and wherein said heterocycle is randomly replaced by one or more low-grade alkyl groups.These heterocycles comprise, for example piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyrrolidyl, isoquinolyl, Diazesuberane base, pyrrolin base, azepan base, the oxygen azepine that randomly replaces
Base and Pyrrolopyrazine base.
According to another embodiment of the present invention, in the compound of formula (I), R
3Expression hydrogen, acyl group, Heterocyclylalkyl, aralkyl, alkoxyl group, alkoxyl group carboxyl, dialkyl amide base, alkylamidoalkyl or heteroaryl.
In one embodiment of the invention, R
3Expression is selected from following group:
In another embodiment of the invention, R
3Expression is selected from following group:
Can prepare compound of the present invention according to one of following method.
Shown in route 1, can obtain the compound of compound and particularly formula (VIII) or the formula (IX) of formula (I), wherein R
1Be monocycle or the polycyclic heteroaryl groups that links to each other with pyrimidine ring by carbon atom, and R
2Be acyclic group, monocycle or the polycyclic heteroaryl groups that links to each other with described pyrimidine ring by nitrogen-atoms.
Route 1
Under 80 ℃-120 ℃ temperature, nitrile that can be by making formula (XI) and trimethyl aluminium and ammonium chloride react the amidine that obtains formula (II), wherein R in solvent such as benzene, toluene or dimethylbenzene
1Be monocycle or the polycyclic heteroaryl groups that links to each other with amidine group by carbon atom.It also can at room temperature react in methyl alcohol by nitrile and the sodium methylate that makes formula (XI), reacts under same temperature with ammonium chloride then to obtain.
In solvent such as methyl alcohol, ethanol, Virahol, butanols or tetrahydrofuran (THF), in the presence of alkali such as sodium methylate, sodium ethylate or potassium tert.-butoxide, and in room temperature to the temperature of described solvent boiling point, the amidine of formula (II) can react with diethyl malonate, with the pyrimidine-4 that obtains formula (III), 6-glycol.
In solvent such as phosphoryl chloride, benzene or toluene, in room temperature to the temperature of described solvent boiling point, the pyrimidine-4 of the formula of gained (III), the 6-glycol can with chlorizating agent such as phosphoryl chloride, phosphorus pentachloride or their mixture reaction, to obtain 4 of formula (IV), 6-dichloro pyrimidine compound.Randomly, in this reactions steps, may need the existence of alkali such as dimethylamino-aniline, triethylamine or diisopropylethylamine.
Under 80 ℃-140 ℃ temperature, in solvent such as methyl alcohol, ethanol, Virahol or tetrahydrofuran (THF), 4 of formula (IV), 6-dichloro pyrimidine compound and ammonium hydroxide reaction obtain the 6-chloropyrimide-4-amine of formula V.
6-chloropyrimide-4-the amine of the formula V of gained and R wherein
2Be acyclic, the monocycle that links to each other with pyrimidine ring by nitrogen-atoms or the formula R of many cyclic groups
2The compound reaction of-H, to obtain the compound of formula (VIII), it is the special case of formula of the present invention (I) compound.In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under the temperature of 60 ℃-140 ℃ of temperature, in solvent such as dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
In solvent such as tetrahydrofuran (THF), methylene dichloride, chloroform or pyridine; in room temperature to the temperature of described solvent boiling point; the compound of formula (VIII) can be by acyl chlorides and alkali such as pyridine, triethylamine or diisopropylethylamine acylations; to obtain the compound of formula (IX), it is the special case of the compound of formula of the present invention (I).Under the temperature of 80 ℃-160 ℃ of temperature, by amine (VIII) and anhydride reaction also can preparation formula (IX) compound.
By with R wherein
2Be acyclic, the monocycle that links to each other with pyrimidine ring by nitrogen-atoms or the formula R of many cyclic groups
2The compound reaction of-H also can be with the compound 4 of formula (IV), and the 6-dichloro pyrimidine is converted into the 4-chloropyrimide of formula (X).In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under 60 ℃-140 ℃ temperature, in solvent such as dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
Then under 80 ℃-140 ℃ temperature, in solvent such as methyl alcohol, ethanol, Virahol or tetrahydrofuran (THF), by with the ammonium hydroxide reaction, the 4-chloropyrimide of the formula (X) of gained can be converted into the compound of formula of the present invention (VIII).
Alternatively, in solvent such as water, methyl alcohol, ethanol or Virahol, to the temperature of described solvent boiling point, compound that also can through type (IX) and mineral acid example hydrochloric acid or sulfuric acid reaction obtain the compound of formula of the present invention (VIII) in room temperature.
The compound of formula of the present invention (IX) can through type (VII) compound and formula R
2The compound of H (R wherein
2As above definition) reaction obtains.In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under 60 ℃-140 ℃ temperature, in solvent such as dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
In the presence of chlorizating agent such as phosphoryl chloride, phosphorus pentachloride or thionyl chloride, under 60 ℃-120 ℃ temperature, 6-aminopyrimidine-4-alkylol cpd and formula R that can through type (VI)
3The carboxylic acid of COOH (R wherein
3As above definition) reacts, obtain the compound of formula (VII).
In turn, the amidine of through type (II) and ethyl cyanacetate reaction and obtain the 6-aminopyrimidine-4-alkylol cpd of formula (VI).In solvent such as methyl alcohol, ethanol, Virahol, butanols or tetrahydrofuran (THF), in the presence of alkali such as sodium methylate, sodium ethylate or potassium tert.-butoxide, and carry out this reaction to the temperature of described solvent boiling point in room temperature.
In solvent such as phosphoryl chloride, benzene or toluene, in room temperature to the temperature of described solvent boiling point, 6-aminopyrimidine-4-the alcohol of the formula of gained (VI) can with chlorizating agent such as phosphoryl chloride, phosphorus pentachloride or their mixture reaction, to obtain the 4-amino-6-chloropyrimidine compound of formula V.Randomly, in this reactions steps, may need alkali such as dimethylamino-aniline, triethylamine or diisopropylethylamine to exist.
In solvent such as tetrahydrofuran (THF), methylene dichloride, chloroform or pyridine; to the temperature of described solvent boiling point, 6-chloropyrimide-4-amine compound that can be by formula V is obtained the compound of formula (VII) by chloride of acid and alkali such as pyridine, triethylamine or diisopropylethylamine acylations in room temperature.Under 80 ℃-160 ℃ temperature, by amine (V) and anhydride reaction also can preparation formula (VII) compound.
According to the compound that can obtain formula (I) shown in the route 2, particularly can obtain the compound of formula (XV), wherein R
1' and R
1" be H, little alkyl or halogen, and X is N or the carbon that randomly replaced by little alkyl, halogen, and R
2Be acyclic, monocycle or the many cyclic groups that links to each other with pyrimidine ring by nitrogen-atoms.
Route 2
At 60 ℃, in the presence of solvent such as NMP, can be by 2,4-two chloro-6-aminopyrimidines react with anhydrous hydrazine, then under the temperature of room temperature to 60 ℃, make intermediate and suitable two reactive ketones obtain the compound of formula (XII).
In solvent such as tetrahydrofuran (THF), methylene dichloride, chloroform or pyridine; to the temperature of described solvent boiling point, 6-chloropyrimide-4-amine compound that can through type (XII) is obtained the compound of formula (XIV) by chloride of acid and alkali such as pyridine, triethylamine or diisopropylethylamine acylations in room temperature.Under 80 ℃-160 ℃ temperature, by amine (XII) and anhydride reaction also can preparation formula (XIV) compound.
6-chloropyrimide-4-the amine of gained formula (XIV) and R wherein
2Be acyclic, the monocycle that links to each other with pyrimidine ring by nitrogen-atoms or the formula R of many cyclic groups
2The compound reaction of-H, to obtain the compound of formula (XV), it is the special case of the compound of formula of the present invention (I).In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under 60 ℃-140 ℃ of temperature, in solvent such as dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
6-chloropyrimide-4-the acid amides of formula (XII) and R wherein
2Be acyclic, the monocycle that links to each other with pyrimidine ring by nitrogen-atoms or the formula R of many cyclic groups
2The compound reaction of-H is to obtain the compound of formula (XIII).In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under 60 ℃-140 ℃ temperature, in solvent such as dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
In solvent such as tetrahydrofuran (THF), methylene dichloride, chloroform or pyridine; in room temperature to the temperature of described solvent boiling point; 4-aminopyrimidine compounds that can through type (XIII) is obtained the compound of formula (XV) by chloride of acid and alkali such as pyridine, triethylamine or diisopropylethylamine acylations, and it is the special case of the compound of formula of the present invention (I).Under 80 ℃-160 ℃ temperature, by amine (XVI) and anhydride reaction also can preparation formula (XV) compound.
According to the compound that can obtain formula (I) shown in the route 3, particularly can obtain the compound of formula (XVIII), wherein R
1' and R
1" be H, little alkyl or halogen, X is nitrogen or the carbon that randomly replaced by H, little alkyl or halogen, R
2Be acyclic, monocycle or the many cyclic groups that links to each other with pyrimidine ring by nitrogen-atoms, and R
3Be COR
6, OR
6, COR
6R
7Or COOR
6
Route 3
Work as R
3When being alkoxyl group, in solvent such as tetrahydrofuran (THF), dimethyl formamide or dioxane, in room temperature to the temperature of described solvent boiling point, the salt that can be by the N-alkoxylamine and the reaction of alkali such as pyridine, triethylamine or diisopropylethylamine are by 4, and 6-two chloro-2-(methylthio group) pyrimidines obtain the compound of formula (XVI).Work as R
3Be COR
6The time; by under 80 ℃-140 ℃ temperature; in solvent such as methyl alcohol, ethanol, Virahol or tetrahydrofuran (THF); make 4; the reaction of 6-two chloro-2-(methylthio group) pyrimidines and ammonium hydroxide, subsequently in solvent such as tetrahydrofuran (THF), methylene dichloride, chloroform or pyridine, in room temperature to the temperature of described solvent boiling point; carry out acylations with chloride of acid and alkali such as pyridine, triethylamine or diisopropylethylamine, compound that can preparation formula (XVI).By under 80 ℃-140 ℃ temperature, in solvent such as methyl alcohol, ethanol, Virahol or tetrahydrofuran (THF), make 4, the reaction of 6-two chloro-2-(methylthio group) pyrimidines and ammonium hydroxide, compound that also can preparation formula (XVI) under 80 ℃-160 ℃ temperature then with anhydride reaction.
Oxygenant as
Hydrogen peroxide, potassium permanganate or Sodium peroxoborate exist down, by methylthio group being oxidized to the compound that sulfone can obtain formula (XVII).Then under 60 ℃ temperature, in the presence of solvent such as NMP, make the reaction of sulfone intermediate and anhydrous hydrazine, and under the temperature of room temperature to 60 ℃, with two suitable reactive ketones.
The 6-chloropyrimide of gained formula (XVII) and R wherein
2Be acyclic, the monocycle that links to each other with pyrimidine ring by nitrogen-atoms or the formula R of many cyclic groups
2The compound reaction of-H, to obtain the compound of formula (XVIII), it is the special case of the compound of formula of the present invention (I).In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under 60 ℃-140 ℃ temperature, in solvent such as dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
According to the compound that can obtain formula (I) shown in the route 4, particularly can obtain the compound of formula (XXI), wherein R
1' and R
1" be H, little alkyl or halogen, and R
2Be acyclic, monocycle or the many cyclic groups that links to each other with pyrimidine ring by nitrogen-atoms.
Route 4
Make 4-amino-2, the 6-dichloro pyrimidine reacts the compound that can obtain formula (XIX) with the pyrazoles that randomly replaces.In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under 60 ℃-140 ℃ temperature, in solvent such as dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
6-chloropyrimide-4-the amine of gained formula (XIX) and R wherein
2Be acyclic, the monocycle that links to each other with pyrimidine ring by nitrogen-atoms or the formula R of many cyclic groups
2The compound reaction of-H is to obtain the compound of formula (XX).In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under 60 ℃-140 ℃ temperature, in solvent such as dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
In solvent such as tetrahydrofuran (THF), methylene dichloride, chloroform or pyridine; to the temperature of described solvent boiling point, 2-pyrazolopyrimidine-4-amine compound that can through type (XX) is obtained the compound of formula (XXI) by chloride of acid and alkali such as pyridine, triethylamine or diisopropylethylamine acylations in room temperature.Work as R
3When being heterocycle, general Buchwald condition is used for linked reaction.Under 80 ℃-160 ℃ temperature, by amine (XX) and anhydride reaction also can preparation formula (XXI) compound, it is the special case of the compound of formula of the present invention (I).
In solvent such as tetrahydrofuran (THF), methylene dichloride, chloroform or pyridine; to the temperature of described solvent boiling point, 6-chloropyrimide-4-amine compound that can through type (XIX) is obtained the compound of formula (XXII) by chloride of acid and alkali such as pyridine, triethylamine or diisopropylethylamine acylations in room temperature.Under 80 ℃-160 ℃ temperature, by amine (XX) and anhydride reaction also can preparation formula (XXII) compound.
The 6-chloro-2-pyrazolopyrimidine of gained formula (XXII) and R wherein
2Be acyclic, the monocycle that links to each other with pyrimidine ring by nitrogen-atoms or the formula R of many cyclic groups
2The compound reaction of-H, to obtain the compound of formula (XXI), it is the special case of the compound of formula of the present invention (I).In the presence of alkali such as sodium hydride, salt of wormwood or cesium carbonate, under 60 ℃-140 ℃ temperature, in solvent such as dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide, carry out this reaction.
Can be according to the acid amides of route 5 preparation formulas (XXIII) and formula (XXIV).
Route 5
In solvent such as methylene dichloride and alkali (as pyridine), the compound of through type (VIII) and chloroacetyl chloride reaction and obtain the acid amides of formula (XXIII).In the presence of salt of wormwood and DMF, the amine that makes the compound of gained formula (XXIII) and expectation is (as NHR
6R
7) reaction, with the acid amides of the formula (XXIV) that obtains expecting.Can be by V, VI, XII, XIII, 4,6-two chloro-2-(methylthio group) pyrimidines, XIX or XX begin, and use the step of same order.
Route 6
The compound of through type (VIII) and formula Z-COOR
6Compound (wherein Z represents leavings group, halogen atom for example, preferred chlorine or be selected from the group of oxyethyl group, methoxyl group, p-nitrophenyl oxygen base and imidazolyl) reaction and obtain the carbamate of formula (XXV).In the presence of alkali, preferred triethylamine, diisopropylethylamine, salt of wormwood or sodium hydroxide, under-70 ℃ to 100 ℃ temperature, in solvent such as tetrahydrofuran (THF), chloroform, methylene dichloride or dimethyl formamide, carry out this reaction.
The compound of through type (VIII) and triphosgene, phosgene and formula HO-R
6Alcohol reaction and obtain the carbamate of formula (XXV).In the presence of alkali, preferred pyridine, under-5 ℃ to 50 ℃ temperature, in solvent such as tetrahydrofuran (THF), chloroform, methylene dichloride or dimethyl formamide, carry out this reaction.
Under the temperature of room temperature to 140 ℃, in solvent such as benzene, toluene or dimethylbenzene, by with formula R
6The isocyanate reaction of-N=C=O also can be converted into wherein R with the compound of formula (VIII)
7It is the urea of the formula (XXVI) of hydrogen atom.
The compound of through type (VIII) and triphosgene, phosgene and formula HNR
6R
7Amine reaction and obtain the urea of formula (XXVI).In the presence of alkali, preferred pyridine, under-5 ℃-50 ℃ temperature, in solvent such as tetrahydrofuran (THF), chloroform, methylene dichloride or dimethyl formamide, carry out this reaction.
Can be by V, VI, XII, XIII, 4,6-two chloro-2-(methylthio group) pyrimidines, XIX or XX begin, and use the step of same order.
As defined R
1To R
7Group is subject to chemical reaction influence or when incompatible with described method under the condition of aforesaid method, can be according to standard practices, for example referring to T.W.Greene and P.G.M.Wuts, ' Protective Groups in Organic Chemistry ', the 3rd edition, John Wiley ﹠amp; Sons (1999) uses the GPF (General Protection False base.Deprotection may be the final step in formula (I) compound synthetic.
Pharmacological activity
Adenosine A
2AReceptors bind is measured
Receptor cloning
Obtain human A by polymerase chain reaction by the amplification of human brain cDNA storehouse
2AThe encoding sequence of acceptor.Amplicons cloned is gone in the pcDNA5/FRT/V5-His-TOPO expression vector (Invitrogen), and utilize ABI 3100 automatic sequencers (Applied Biosystems) to confirm sequence.With LipofectAMINE2000 (Invitrogen) expression construct is transfected in the Flp-In HEK cell (Invitrogen).Screening the human A of stably express among the DMEM fully with the 1mg/ml Totomycin
2AThe cell of acceptor.
Membrane prepare
By cell being resuspended to molten born of the same parents' damping fluid (50mM Tris-HCl pH 7.4,5mM EDTA, 10mM MgCl
2), on ice in N
2(Parr cytoclasis bomb (bomb), cat.4639) following broken 30min is then by differential centrifugation, from using human A for air pressure 900psi
2AThe Flp-InHEK cell preparation crude product film of acceptor transfection.Gained crude product film small pieces are resuspended to mensuration damping fluid (50mM TrisHCl pH 7.4,1mM EDTA, 10mM MgCl
2) in.Measure membranin concentration by the Bradford assay method, and-80 ℃ of storage aliquots containigs.
In conjunction with measuring
(Type IV Calf Spleen Sigma) exists down, at room temperature preincubation film aliquots containig (5-10 μ g albumen) 30min at 10 μ g/ml adenosine deaminases.Then, in the presence of the competition part of different concns, with film and 1.0nM [
3H]-ZM 241385 (27.40Ci/mmol Tocris R
1036) incubation 90min together.In the presence of excessive CGS15943 (1 μ M), measure non-specific binding.Use Packard96 porocyte collector, filter by fast vacuum, separation and combination part and free ligand are extremely with on the pretreated UniFilter GF/C of the 0.5% polymine screen plate (PerkinElmer).Use 50mMTris HCl, 50mM NaCl pH 7.4 washing and filtering plates (3x200 μ l) then.Use TopCount-NXT (Packard) to measure the bonded radioligand by scintillation counting.Use GraphPad Prism (GraphPad Software, Inc.San Diego, CA) or ActivityBase (Surrey UK), analyzes binding data by the nonlinear least square method curve fitting algorithm for IDBS, Guildford.Utilize Cheng-Prusoff equation (Cheng, Y, Prusoff, W.H.Biochem.Pharm.22:3099-3108,1973.), by IC
50Value calculates K
iValue.
A
2AFilm is measured:
Analyze the Kd=0.3 ± 0.2nM that records ZM241385 by Scatchard; B
Max=33 ± 8pmol/mg.
In conjunction with Ki=0.25 ± 0.04nM.
About A
2AReceptor affinity, A of the present invention
2AReceptor antagonist can have the Ki less than 10 μ M.In an embodiment of the present invention, A
2AReceptor antagonist has the Ki less than 1 μ M.In another embodiment, A
2AReceptor antagonist has the Ki less than 100nM, and in yet another embodiment, A
2AReceptor antagonist has the Ki less than 10nM.
Pyrimidine of the present invention-4-sulfonamide derivatives is used for the treatment of or prevents known being easy to by treat the disease of improving with adenosine receptor antagonists, and particularly those are easy to by using A
2AAdenosine receptor antagonists is treated the disease of improving.These diseases are that for example ischemic, supraventricular arrhythmia, acute renal failure, reperfusion injury of cardiac muscle, anaphylaxis are including, but not limited to rhinitis, urticaria, scleroderma sacroiliitis (scleroderm arthritis), other autoimmune disorder, inflammatory bowel disease, asthma, diabetes, obesity, Parkinson's disease, Huntington Chorea, dystonia such as restless leg syndrome, dyskinesia or the somnopathy of dyskinesia as causing by taking psychosis and dopaminergic medicine for a long time.
Therefore, compound of the present invention and pharmacologically acceptable salts thereof, and the pharmaceutical composition that comprises these compounds and/or its salt can be used in the treatment conditions of human body method in, this method comprises to the compound of the present invention of the individual effective dosage of the such treatment of needs or its pharmacologically acceptable salts.
The present invention also provides such pharmaceutical composition, and described pharmaceutical composition comprises compound or its pharmacologically acceptable salts and the acceptable vehicle of pharmacy such as the carrier or the thinner of the formula (I) as activeconstituents.Depend on the character of preparation and before using, whether will further dilute that described activeconstituents can constitute the 0.001%-99% of described composition weight, preferred 0.01%-90%.Described composition preferably be mixed be suitable for oral, local, nasal cavity, rectum, through the formulation of skin or drug administration by injection.
The acceptable vehicle of pharmacy that mixes to form the present composition with the salt of described active compound or described compound is well-known in the art, and the actual vehicle that uses depends on the described method for compositions of the administration that is intended to use except that other factors.
Composition of the present invention preferably is suitable for injectable and oral administration.In this case, be used for liquid preparations for oral administration and can adopt for example form of mixture, elixir, syrup or suspensoid of tablet, slow releasing tablet, sublingual tablet, capsule, inhalation aerosol, solution for inhalation, Foradil Aerolizer formoterol fumarate or liquid preparation, all preparations all comprise compound of the present invention; Can prepare these preparations according to method well known in the art.
The thinner that can be used for described composite preparation comprises liquid and the solid diluent that those are compatible with described activeconstituents, if desired, comprises tinting material or seasonings simultaneously.Tablet or capsule can comprise the salt of 2-500mg activeconstituents or its equivalent easily.
The liquid composition that is suitable for orally using can be the form of solution or suspensoid.Described solution can be the soluble salt of described active compound or the aqueous solution of other derivative, is combined to form syrup with for example sucrose.Described suspensoid can comprise insoluble active compound of the present invention or its pharmacologically acceptable salts, water and suspending agent or seasonings.
The composition that is used for parenteral injection can and get by soluble salt preparation, and described composition is can yes or no freeze dried, and it can be dissolved in no heat source water medium or other is suitable for the liquid of parenteral injection.
Effective dose is generally in the scope of 2-2000mg activeconstituents every day.Per daily dose can the every day of administration in one or many treatment, preferred 1-4 treatment.
Further specify the present invention by following examples.Only provide these embodiment and should not be construed as restriction as example.
Reagent, raw material and solvent are all bought from commercial supplier and are used the former state that receives.Concentrate and be meant under vacuum with the evaporation of B ü chi rotatory evaporator.If desired, reaction product goes up with the solvent systems that illustrates at silica gel (40-63 μ m) and passes through purified by flash chromatography.On Varian Mercury 300MHz spectrometer and Bruker Avance 500MHz spectrometer, write down spectral data.
Analyze HPLC-MS method 1
Platform: Agilent 1100 series: dispose automatic sampler, UV detector (220nM and 254nM), MS detector (APCI);
HPLC post: Phenomenex Synergi-Max RP, 2.0x50mm post;
HPLC gradient: 1.0mL/ minute, in 13.5 minutes,, kept 2 minutes 95% by 5% acetonitrile/water to 95% acetonitrile/water.All contain 0.025%TFA in acetonitrile and the water.
Analyze HPLC-MS method 2
Platform: Dionex: dispose automatic sampler, UV detector (220nM and 254nM), MS detector (APCI);
HPLC post: Phenomenex CX184.6x150mm;
HPLC gradient: 9.86min, 95%0.04%NH
4OH/H2O to 90%0.04%NH
4OH/CAN, operation 12.30min
Analyze HPLC-MS method 3
Platform: Agilent 1100 series: dispose automatic sampler, UV detector (220nM and 254nM), MS detector (APCI);
HPLC post: Phenomenex Synergi-Max RP, 2.0x50mm post;
HPLC gradient: 1.0mL/ minute, in 2.5 minutes,, kept 1 minute 90% by 10% acetonitrile/water to 90% acetonitrile/water.All contain 0.025%TFA in acetonitrile and the water.
Analyze HPLC-MS method 4
Platform: Agilent 1100 series: dispose automatic sampler, UV detector (230nM and 254nM), MS detector (APCI);
HPLC post: Phenomenex Synergi-Max RP, 2.0x50mm post;
The HPLC gradient: solvent C is 6mM ammonium formiate/water, and solvent D is 25% acetonitrile/methanol.Gradient to 95%D (5%C), kept 1.02min at 95%D by 5%D (95%C) in 6.43 minutes, reply subsequently and keep 1.52min at 5%D.
Intermediate 1:6-chloro-2-(3-1-yl) pyrimidine-4-base amine
(the 6-dichloro pyrimidine is dissolved in the 200mL N-Methyl pyrrolidone for 0.24mol, 1eq) 4-amino-2 with 40.0g.Heat this soup compound to 60 ℃, slowly add 19.14mL (0.61mol, 2.5eq.) anhydrous hydrazine then.1.5 after hour, reinforced finishing.The reaction be cooled to room temperature, slowly add then 62.6mL (0.61mol, 2.5eq.) 2, the 4-diacetylmethane remains on below 50 ℃ temperature of reaction.After 1 hour, reacting by heating to 50 ℃ adds 200mL ethanol then once more, adds 400mL water subsequently.After adding water and finishing, reaction mixture is to room temperature, in filtration on paper.With alcohol/water (3x200mL) washing leaching cake, spend the night 60 ℃ of vacuum-dryings then.The brown solid that reclaims is the regional isomer (43.2g, the 85 area % purity at the 254nm place) of expection and the mixture of 4-dimethyl pyrazole regional isomer.Product recrystallization and obtain white solid (yield 66%) from hot THF/i-PrOAc.LCMS (method 3) m/z 223.9[MH+], Tr=1.97min.
Intermediate 2.6-chloro-2-(3,4,5-trimethylammonium pyrazol-1-yl) pyrimidine-4-base amine
According to above about intermediate 1 described identical method, with 3-methyl-2, the 4-diacetylmethane replaces 2,4-diacetylmethane, preparation intermediate 2.LCMS (method 3) m/z 237.9[MH+], Tr=2.38min.
Intermediate 3.6-chloro-2-(4-chloro-3-1-yl) pyrimidine-4-base amine
According to above about intermediate 1 described identical method, with 3-chloro-2, the 4-diacetylmethane replaces 2, the 4-diacetylmethane prepares intermediate 3.LCMS (method 3) m/z 257.7[MH+], Tr=2.61min.
Intermediate 4.6-chloro-2-(3,5-dimethyl-[1,2,4] triazol-1-yl) pyrimidine-4-base amine
According to above about intermediate 1 described identical method, replace 2 with diacetamide, the 4-diacetylmethane prepares intermediate 4.LCMS (method 3) m/z 224.8[MH+], Tr=1.96min
Intermediate 5:N-[6-chloro-2-(3,5-dimethyl-pyrazol-1-yl) pyrimidine-4-yl] ethanamide
(0.18mol, 1eq.) 6-chloro-2-(3-1-yl) pyrimidine-4-base amine is dissolved in 200mL, and (0.9mol, 5eq.) acetate stir under the room temperature then with 40.0g.(0.8mol, 4.7eq.) diacetyl oxide is then 90 ℃ of these mixture overnight of heating to add 80mL.Reaction is cooled to room temperature with it after finishing, and adds 16mL water then in 30 minutes.Pass through this mixture of filter paper filtering, water (4x75mL) washing leaching cake then.Dry this solid spends the night in 50 ℃ of vacuum drying ovens.The solvate of AcOH (48.2g, 0.15mol, 83% yield) is a canescence crystalline solid.LCMS (method 3) m/z 265.9[MH+], Tr=2.11min.
Intermediate 6.N-[6-chloro-2-(3,4,5-trimethylammonium pyrazol-1-yl) pyrimidine-4-yl] ethanamide
According to the method described in the intermediate 5, replace 6-chloro-2-(3-1-yl) pyrimidine-4-base amine to prepare intermediate 6 with intermediate 2.LCMS (method 3) m/z 279.8[MH+], Tr=2.55min.
Intermediate 7.N-[6-chloro-2-(4-chloro-3-1-yl) pyrimidine-4-yl] ethanamide
According to the method described in the intermediate 5, replace 6-chloro-2-(3-1-yl) pyrimidine-4-base amine to prepare intermediate 7 with intermediate 3.LCMS (method 3) m/z 299.8[MH+], Tr=2.71min.
Intermediate 8.N-[6-chloro-2-(3,5-dimethyl-[1,2,4] triazol-1-yl) pyrimidine-4-yl] ethanamide
According to the method described in the intermediate 5, replace 6-chloro-2-(3-1-yl) pyrimidine-4-base amine to prepare intermediate 7 with intermediate 4.LCMS (method 3) m/z 266.8[MH+], Tr=2.18min.
Intermediate 9:N-[6-chloro-2-(3-1-yl) pyrimidine-4-yl] propionic acid amide
(16.3mmol, 1.2eq.) propionyl chloride slowly joins 1.3mL (16.3mmol, 1.2eq.) (13.6mmol is 1eq.) in the cold DMF solution (30mL) of intermediate 1 for anhydrous pyridine and 3.0g with 1.4mL.Stir this mixture overnight under the room temperature.After reacting completely, neutralize this reaction mixture to pH 7, use methylene dichloride (3x50mL) extraction product then with saturated sodium bicarbonate aqueous solution.Merge organic layer, use dried over mgso, concentrate then.Is eluent purifying by column chromatography with the methylene dichloride that contains 2% methyl alcohol with silica gel, obtains the light brown solid of 3.4g (75% yield).LCMS (method 1) m/z 280.0[MH+], Tr=6.08min.
Intermediate 10:N-[6-chloro-2-(3-1-yl) pyrimidine-4-yl]-3-methylbutyryl amine
According to the similar methods that is used for intermediate 9, prepare intermediate 9 by intermediate 1 and isobutyryl chloride are reacted.With the mixture of 1/1 ethyl acetate/hexane,, obtain white solid with similar yield by liquid phase chromatography purifying residuum.LCMS (method 1) m/z 308.1[MH+], Tr=7.44min.
Intermediate 11:2-chloro-N-[6-chloro-2-(3-1-yl) pyrimidine-4-yl] ethanamide
At 0 ℃, to intermediate 1 (1.9g, 8.7mmol, methylene dichloride 1eq.) (100mL) solution add pyridine (0.9mL, 11.7mmol, 1.3eq.), drip subsequently chloroacetyl chloride (1.1mL, 13.5mmol, 1.5eq.).Make this mixture be warmed to room temperature, stirring is spent the night.After reaction is finished, cool off this solution to 0 ℃, use the saturated NaHCO of 25mL then carefully with ice bath
3Aqueous solution termination reaction.(3x 25mL) extracts this reaction solution with methylene dichloride.With the organic layer that the salt water washing merges, use dried over mgso, filter, concentrate then.With the methylene dichloride that contains 10% methyl alcohol,, obtain 2-chloro-N-[4-chloro-2-(3-1-yl) pyrimidine-4-yl with 92% yield by silica gel chromatography purifying residuum] ethanamide, be yellow solid.LCMS (method 3) m/z 300.0[MH+], Tr=2.69min.
Intermediate 12:N-[6-chloro-2-(3-1-yl) pyrimidine-4-yl]-2-morpholine-4-yl acetamide
(3.0g, 13mmol 1eq.) are dissolved in methylene dichloride (25mL) with intermediate 11.Under the room temperature, be added dropwise to morpholine (1.2mL, 14mmol, 1.1eq.) and diisopropylamine (4.6mL, 26mmol, 2.0eq.).After stirring was spent the night, water made this solution layering, used methylene dichloride (3x25mL) extraction then.With the organic layer that salt solution (50mL) washing merges, drying is filtered, then concentrating under reduced pressure.Make eluent with methylene dichloride, pass through silica gel chromatography purifying residuum, obtain 1.5g (33% yield) intermediate 12 with the gradient of methyl alcohol (2-5%).LCMS (method 3) m/z 300.0[MH+], Tr=2.69min.
Intermediate 13:N-[6-chloro-2-(3-1-yl) pyrimidine-4-yl]-2-(4-methylpiperazine-1-yl) ethanamide
According to the similar methods that is used for intermediate 12, by making intermediate 11 and N-methyl piperidine prepared in reaction intermediate 13.LCMS (method 2) m/z 363.6[MH+], Tr=7.34min.
Intermediate 14:N-[6-chloro-2-(3-1-yl) pyrimidine-4-yl]-2-(tetramethyleneimine-1-yl) ethanamide
According to the similar methods that is used for intermediate 12, by making intermediate 11 and tetramethyleneimine prepared in reaction intermediate 14.
Compound 1-3:N-[2-(3-1-yl)-6-(2-(R)-methoxymethyl) tetramethyleneimine-1-base-pyrimidine-4-yl] ethanamide
(50mg, 0.19mmol 1eq.) are dissolved in exsiccant dioxane (2mL) with intermediate 5.Add 1.2eq (26mg, 0.23mmol) (R)-2-methoxymethyl tetramethyleneimine.Heat these mixtures 2 hours at 80 ℃, be cooled to room temperature, filter, use the HPLC purifying then.LCMS (method 2) m/z 345.0[MH+], Tr=6.23min.
Compound 1-14:N-[2-(3-1-yl)-6-(2-oxo-pyrrolidine-1-yl) pyrimidine-4-yl] ethanamide
At 100 ℃, intermediate 4 (50mg, the 0.19mmol of heating in dry toluene (2mL), 1eq.), lactan (81mg, 0.95mmol, 5eq.), acid chloride (5mg, 0.02mmol, 0.1eq), 4, two (diphenylphosphine)-9 of 5-, 9-dimethyl xanthene (17mg, 0.03mmol, 0.15eq), cesium carbonate (68mg, 0.21mmol, mixture overnight 1.1eq).
After returning back to room temperature and filtration, by this mixture of HPLC purifying.LCMS (method 2) m/z315.2[MH+], Tr=5.31min.
Compound 1-51:N-[2-(3-1-yl)-6-tetramethyleneimine-1-yl pyrimidines-4-yl] ethanamide
(50mg, 0.19mmol 1eq.) are dissolved in exsiccant dioxane (2mL) with intermediate 5.Add 1.1eq. (68mg, 0.21mmol) cesium carbonate and 1.1eq (15mg, 0.21mmol) tetramethyleneimine.Until end, be cooled to room temperature at 80 ℃ of these mixtures of heating, filter, then by the HPLC purifying.LCMS (method 1) m/z 301.1[MH+], Tr=4.88min.
By making suitable above-mentioned intermediate and suitable by substituent R
2The compound of the amine prepared in reaction table 1A of expression:
Table 1A
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-1 | ??5 | 3-fluoro-2-p-methoxy-phenyl amino | ??370.4 | ??371.3 | ?8.1 | ??2 |
| ??1-2 | ??5 | 3,4-dihydro-1H-isoquinoline 99.9-2-base | ??362.4 | ??363.3 | ?10.1 | ??2 |
| ??1-3 | ??5 | (R)-2-methoxymethyl-tetramethyleneimine-1-base | ??362.4 | ??362.9 | ?7.6 | ??1 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-4 | ??5 | 2-methyl-2,3-indoline-1-base | ??344.4 | ??345.2 | ??6.4 | ??2 |
| ??1-5 | ??5 | 2-oxo-2,3-indoline-1-base | ??358.4 | ??359.1 | ??8.0 | ??2 |
| ??1-6 | ??5 | 3-p-methoxy-phenyl amino | ??362.4 | ??363.1 | ??6.2 | ??1 |
| ??1-7 | ??5 | Phenyl amino | ??352.4 | ??352.8 | ??7.8 | ??2 |
| ??1-8 | ??5 | 1,3-xylylenimine-2-base | ??322.4 | ??323.8 | ??7.7 | ??2 |
| ??1-9 | ??5 | 2-methoxymethyl tetramethyleneimine-1-base | ??401.5 | ??402.3 | ??8.7 | ??2 |
| ??1-10 | ??5 | 2-oxo-piperidine-1-base | ??344.4 | ??344.8 | ??5.0 | ??1 |
| ??1-11 | ??5 | 2-fluorophenyl amino | ??328.4 | ??329.6 | ??5.0 | ??1 |
| ??1-12 | ??5 | 2-p-methoxy-phenyl amino | ??340.4 | ??340.8 | ??7.6 | ??2 |
| ??1-13 | ??5 | (2R, 5R)-2,5-pair-methoxymethyl tetramethyleneimine-1-base | ??352.4 | ??352.8 | ??7.7 | ??2 |
| ??1-14 | ??5 | 2-oxo-pyrrolidine-1-base | ??388.5 | ??389.1 | ??7.5 | ??1 |
| ??1-15 | ??5 | 2-propyl pyrrole alkane-1-base | ??429.5 | ??429.9 | ??4.4 | ??1 |
| ??1-16 | ??5 | Two (2-methoxy ethyl) amino | ??1 | |||
| ??1-17 | ??5 | (2R, 4R)-4-methoxyl group-2-methoxymethyl tetramethyleneimine-1-base | ??412.4 | ??412.8 | ??6.3 | ??1 |
| ??1-18 | ??5 | (3-hydroxyl-3-phenyl propyl) methylamino | ??1 | |||
| ??1-19 | ??5 | 3,6-dihydro-2H-pyridine-1-base | ??374.4 | ??375.1 | ??4.8 | ??1 |
| ??1-20 | ??5 | 3-methoxy methyl phenylpiperidines-1-base | ??312.4 | ??312.8 | ??7.7 | ??1 |
| ??1-21 | ??5 | (R)-2-hydroxymethyl-pyrrolidine-1-base | ??358.4 | ??358.7 | ??7.7 | ??1 |
| ??1-22 | ??5 | 2-propyl pyrrole alkane-1-base | ??1 | |||
| ??1-23 | ??5 | 3,5-lupetidine-1-base | ??330.4 | ??330.8 | ??4.2 | ??1 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-24 | ??5 | 3-oxo-2-azaspiro [4.5] last of the ten Heavenly stems-2-base | ??342.4 | ??343.3 | ??7.8 | ??2 |
| ??1-25 | ??5 | (R)-2-methoxy methyl phenylpiperidines-1-base | ??382.5 | ??383.1 | ??8.7 | ??1 |
| ??1-26 | ??5 | 2-methylpyrrolidin-1-yl) pyrimidine-4-base | ??358.4 | ??359.1 | ??5.3 | ??1 |
| ??1-27 | ??5 | (3-hydroxyl-3-phenyl propyl) methylamino | ??366.4 | ??367.1 | ??6.3 | ??1 |
| ??1-28 | ??5 | 4-p-methoxy-phenyl amino | ??455.0 | ??455.0 | ??5.4 | ??1 |
| ??1-29 | ??5 | Two (2-methoxy ethyl) amino | ??330.4 | ??330.9 | ??4.1 | ??1 |
| ??1-30 | ??5 | 2-Yang Dai oxazolidine-3-base | ??362.4 | ??363.0 | ??8.1 | ??2 |
| ??1-31 | ??5 | 3-methyl piperidine-1-base | ??316.3 | ??317.5 | ??4.5 | ??1 |
| ??1-32 | ??5 | 2-methoxy methyl phenylpiperidines-1-base | ??328.4 | ??329.0 | ??7.4 | ??2 |
| ??1-33 | ??5 | Sec.-propyl-(2-methoxy ethyl) amino | ??386.5 | ??387.4 | ??9.1 | ??2 |
| ??1-34 | ??5 | Methoxyl group amino | ??330.4 | ??331.1 | ??6.4 | ??1 |
| ??1-35 | ??5 | 6-methoxypyridine-3-base is amino | ??346.4 | ??347.4 | ??7.7 | ??1 |
| ??1-36 | ??5 | Ethyl (2-methoxy ethyl) amino | ??353.4 | ??354.1 | ??6.9 | ??2 |
| ??1-37 | ??5 | Oxyethyl group amino | ??332.4 | ??333.3 | ??8.6 | ??2 |
| ??1-38 | ??5 | 3-trifluoromethyl-5,6-dihydro-8H-[1,2,4] triazolo [4,3-a] pyrazine-7-base | ??290.3 | ??291.2 | ??6.3 | ??1 |
| ??1-39 | ??5 | (tetrahydrofuran (THF)-2-ylmethyl) amino | ??421.4 | ??422.1 | ??4.9 | ??1 |
| ??1-40 | ??5 | 2-ethyl piperidine-1-base | ??413.5 | ??414.2 | ??4.5 | ??1 |
| ??1-41 | ??5 | Piperidines-1-base | ??342.4 | ??343.3 | ??7.7 | ??2 |
| ??1-42 | ??5 | 3-methoxyl group piperidines-1-base | ??314.4 | ??314.9 | ??5.4 | ??1 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-43 | ??5 | 2-methoxyl group-1-phenylethyl amino | ??344.4 | ??344.9 | ??4.8 | ??1 |
| ??1-44 | ??5 | (2-hydroxyethyl) methylamino | ??380.4 | ??381.4 | ??7.6 | ??1 |
| ??1-45 | ??5 | [1,3]-dioxolane-2-ylmethyl methylamino | ??304.4 | ??304.9 | ??5.4 | ??2 |
| ??1-46 | ??5 | Diethylamino | ??346.4 | ??346.9 | ??7.9 | ??2 |
| ??1-47 | ??5 | 2-carboxyl-4-hydroxyl pyrrolidine-1-base | ??302.4 | ??302.8 | ??9.1 | ??2 |
| ??1-48 | ??5 | (R)-2-isopropoxy methylpyrrolidin-1-base | ??360.4 | ??360.1 | ??6.0 | ??1 |
| ??1-49 | ??5 | (2R, 4R)-2-hydroxymethyl-4-methoxyl group tetramethyleneimine-1-base | ??372.5 | ??372.9 | ??5.1 | ??1 |
| ??1-50 | ??5 | (S)-3-fluoropyrrolidine-1-base | ??360.4 | ??361.0 | ??4.0 | ??1 |
| ??1-51 | ??5 | Tetramethyleneimine-1-base | ??318.4 | ??319.0 | ??4.8 | ??1 |
| ??1-52 | ??5 | 4-pyridine-2-base-piperazine-1-base | ??372.5 | ??373.0 | ??7.8 | ??2 |
| ??1-53 | ??5 | (R)-and 1-(tetrahydrofuran (THF)-2-yl) methyl] amino | ??332.5 | ??333.2 | ??9.0 | ??2 |
| ??1-54 | ??5 | 4,4-diethyl-2-oxo-pyrrolidine-1-base | ??330.4 | ??331.0 | ??4.5 | ??1 |
| ??1-55 | ??5 | 3-hydroxy piperidine-1-base | ??372.5 | ??373.5 | ??7.8 | ??1 |
| ??1-56 | ??5 | (R)-2-carboxylate methyl ester-tetramethyleneimine-1-base | ??330.4 | ??331.0 | ??5.8 | ??2 |
| ??1-57 | ??5 | (R)-3-dimethylamino tetramethyleneimine-1-base | ??358.4 | ??358.8 | ??6.9 | ??1 |
| ??1-58 | ??5 | Dimethylamino | ??371.4 | ??371.8 | ??5.9 | ??2 |
| ??1-59 | ??5 | (R)-3-dimethylamino tetramethyleneimine-1-base | ??358.4 | ??358.9 | ??4.7 | ??1 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-60 | ??5 | 2-ethoxyl methyl tetramethyleneimine-1-base | ??330.4 | ??331.0 | ??4.5 | ??1 |
| ??1-61 | ??5 | 4-methoxy methyl phenylpiperidines-1-base | ??358.4 | ??358.9 | ??5.5 | ??1 |
| ??1-62 | ??5 | (R)-2-(2-methoxy ethyl) piperidines-1-base | ??358.4 | ??358.7 | ??7.5 | ??2 |
| ??1-63 | ??5 | Morpholine-4-base | ??405.5 | ??406.5 | ??8.5 | ??2 |
| ??1-64 | ??5 | (S)-2-methoxymethyl tetramethyleneimine-1-base | ??316.4 | ??317.5 | ??6.2 | ??2 |
| ??1-65 | ??5 | 4-phenyl-3,6-dihydro-2H-pyridine-1-base | ??344.4 | ??345.6 | ??6.3 | ??2 |
| ??1-66 | ??5 | 2,6-thebaine-4-base | ??388.5 | ??389.5 | ??10.3 | ??2 |
| ??1-67 | ??5 | (pyridin-4-yl methyl) amino | ??342.5 | ??342.9 | ??9.2 | ??2 |
| ??1-68 | ??5 | Azetidine-1-base | ??412.5 | ??413.1 | ??4.0 | ??1 |
| ??1-69 | ??5 | Ethylpyridine-4-ylmethyl amino | ??286.3 | ??286.9 | ??6.7 | ??2 |
| ??1-70 | ??5 | 2-ethoxyl methyl tetramethyleneimine-1-base | ??365.4 | ??366.4 | ??6.6 | ??2 |
| ??1-71 | ??5 | 4-Phenylpiperidine-1-base | ??358.4 | ??359.4 | ??8.0 | ??2 |
| ??1-72 | ??5 | 4-methoxyl group piperidines-1-base | ??328.4 | ??328.9 | ??8.3 | ??1 |
| ??1-73 | ??5 | 2-carboxylic acid, ethyl ester-piperidines-1 base | ??344.4 | ??345.2 | ??6.8 | ??2 |
| ??1-74 | ??5 | (R)-2-(1-hydroxyl-1-methylethyl) tetramethyleneimine-1-base | ??330.4 | ??331.5 | ??6.8 | ??2 |
| ??1-75 | ??5 | 1-oxo-1,3-dihydro-isoindole-2-base | ??362.4 | ??363.3 | ??10.1 | ??2 |
| ??1-76 | ??5 | 2-methoxymethyl-2,3-indoline-1-base | ??392.5 | ??392.9 | ??6.3 | ??1 |
| ??1-77 | ??9 | 2-methyl-2,3-indoline-1-base | ??376.5 | ??377.2 | ??9.8 | ??2 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-78 | ??9 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??358.4 | ??359.1 | ??8.0 | ??2 |
| ??1-79 | ??5 | (2S, 4R)-4-methoxyl group-2-methoxymethyl tetramethyleneimine-1-base | ??374.4 | ??375.1 | ??4.9 | ??1 |
| ??1-80 | ??9 | 6-cyano group-3,4-dihydro-1H-isoquinoline 99.9-2-base | ??401.5 | ??402.3 | ??8.7 | ??2 |
| ??1-81 | ??12 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??429.5 | ??429.9 | ??4.4 | ??1 |
| ??1-82 | ??1 | (R)-2-isopropoxy methylpyrrolidin-1-base | ??330.4 | ??330.9 | ??4.1 | ??1 |
| ??1-83 | ??5 | Ethanoyl-(3-fluoro-2-p-methoxy-phenyl) amino | ??412.4 | ??412.8 | ??6.3 | ??1 |
| ??1-84 | ??5 | (3-p-methoxy-phenyl) methylamino | ??366.4 | ??367.1 | ??6.3 | ??1 |
| ??1-85 | ??13 | (3-chloro-phenyl-amino) | ??455.0 | ??455.0 | ??5.4 | ??1 |
| ??1-86 | ??5 | (S)-2-hydroxymethyl-pyrrolidine-1-base | ??330.4 | ??330.9 | ??4.1 | ??1 |
| ??1-87 | ??13 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??442.6 | ??443.3 | ??7.5 | ??2 |
| ??1-88 | ??10 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??386.5 | ??387.4 | ??9.1 | ??2 |
| ??1-89 | ??14 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??413.5 | ??414.2 | ??4.5 | ??1 |
| ??1-90 | ??10 | (S)-2-hydroxymethyl-pyrrolidine-1-base | ??372.5 | ??373.0 | ??7.8 | ??2 |
| ??1-91 | ??5 | (1-phenylethyl amino) pyrimidine-4-base | ??350.4 | ??351.5 | ??8.1 | ??2 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-92 | ??5 | (S)-3-methoxyl group tetramethyleneimine-1-base | ??330.4 | ??331.0 | ??4.5 | ??1 |
| ??1-93 | ??10 | (R)-2-hydroxymethyl-pyrrolidine-1-base | ??372.5 | ??373.4 | ??7.8 | ??1 |
| ??1-94 | ??9 | (S)-3-kharophen tetramethyleneimine-1-base | ??371.4 | ??371.8 | ??5.9 | ??2 |
| ??1-95 | ??9 | Morpholine-4-base | ??330.4 | ??331.5 | ??6.8 | ??2 |
| ??1-96 | ??1 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??302.4 | ??302.9 | ??7.0 | ??2 |
| ??1-97 | ??5 | (R)-3-methoxyl group tetramethyleneimine-1-base | ??330.4 | ??331.0 | ??4.5 | ??1 |
| ??1-98 | ??5 | 4-benzyl diethylenediamine-1-base | ??405.5 | ??406.5 | ??8.5 | ??2 |
| ??1-99 | ??5 | 4-phenylpiperazine-1-base | ??391.5 | ??392.3 | ??8.7 | ??2 |
| ??1-100 | ??10 | Tetramethyleneimine-1-base | ??342.4 | ??342.9 | ??9.2 | ??2 |
| ??1-101 | ??13 | 2-oxo-pyrrolidine-1-base | ??412.5 | ??413.1 | ??4.0 | ??1 |
| ??1-102 | ??12 | (S)-2-methoxymethyl tetramethyleneimine-1-base | ??429.5 | ??429.9 | ??4.4 | ??1 |
| ??1-103 | ??1 | 4,4-diethyl-2-oxo-pyrrolidine-1-base | ??328.4 | ??328.9 | ??8.3 | ??1 |
| ??1-104 | ??10 | Morpholine-4-base | ??358.4 | ??359.2 | ??7.9 | ??2 |
| ??1-105 | ??5 | (RS)-2-methoxymethyl-4-methylpyrrolidin-1-base | ??358.4 | ??359.0 | ??5.6 | ??4 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-106 | ??5 | (R)-2-methoxymethyl-4-methylene pyrrolidine-1-base | ??359.4 | ??357.0 | ??5.6 | ??4 |
| ??1-107 | ??5 | (R)-2-methoxymethyl-4-oxo-pyrrolidine-1-base | ??358.4 | ??358.9 | ??4.5 | ??4 |
| ??1-108 | ??5 | (S)-the 4-hydroxyl-(R)-2-methoxymethyl tetramethyleneimine-1-base | ??360.4 | ??361.0 | ??4.3 | ??4 |
| ??1-109 | ??5 | (R)-the 4-hydroxyl-(R)-2-methoxymethyl tetramethyleneimine-1-base | ??360.4 | ??361.0 | ??4.1 | ??1 |
| ??1-110 | ??5 | (R)-the 4-benzyloxy-(R)-2-methoxymethyl tetramethyleneimine-1-base | ??450.5 | ??451.0 | ??6.8 | ??1 |
| ??1-111 | ??5 | (S)-2-benzyloxymethyl tetramethyleneimine-1-base | ??420.5 | ??421.0 | ??6.2 | ??1 |
| ??1-112 | ??5 | (R)-2-benzyloxymethyl tetramethyleneimine-1-base | ??420.5 | ??421.0 | ??6.2 | ??1 |
| ??1-113 | ??5 | (S)-2-(pyridine-2-base oxygen ylmethyl) tetramethyleneimine-1-base | ??407.5 | ??408.0 | ??5.7 | ??1 |
| ??1-114 | ??5 | (R)-2-(pyridine-2-base oxygen ylmethyl) tetramethyleneimine-1-base | ??407.5 | ??407.9 | ??5.6 | ??1 |
| ??1-115 | ??5 | 2-methoxymethyl-2-methylpyrrolidin-1-base | ??344.4 | ??345.0 | ??4.8 | ??1 |
| ??1-116 | ??1 | (S)-2-benzyloxymethyl tetramethyleneimine-1-base | ??378.5 | ??379.0 | ??5.3 | ??1 |
| ??1-117 | ??5 | (R)-2-methyl methoxy base-4-methylene pyrrolidine-1-base | ??356.4 | ??357.0 | ??5.6 | ??4 |
By making suitable above-mentioned intermediate and suitable by substituent R
3The compound of the amine prepared in reaction table 1B of expression.
Table 1B
| Compound number | Intermediate | ??R 3 |
| ??1-200 | ??5 | 2-methoxymethyl-3-methylpyrrolidin-1-base |
| ??1-201 | ??5 | 2-methoxymethyl-5-methylpyrrolidin-1-base |
| ??1-202 | ??5 | 2-methoxymethyl-4-oxyethyl group tetramethyleneimine-1-base |
| ??1-203 | ??5 | 2-methoxymethyl-4-sec.-propyl oxygen base tetramethyleneimine-1-base |
| ??1-204 | ??5 | 4-(2-methoxy ethoxy oxyethyl group)-2-methoxymethyl tetramethyleneimine-1-base |
| ??1-205 | ??5 | (R)-and 2-methyl methoxy base-4-[1-phenylmethylene] tetramethyleneimine-1-base |
Compound-1-96:2-(3-1-yl)-6-((R)-2-methoxymethyl tetramethyleneimine-1-yl) pyrimidine-4-base amine
80 ℃ of heating intermediates 1 (25mg, 0.11mmol, 1eq.) and (R)-2-methoxymethyl tetramethyleneimine (23mg, 0.27mmol, ethanol 2.5eq.) (1.5mL) solution 3 hours.After returning back to room temperature, filter this solution, then by the HPLC purifying.LCMS (method 2) m/z 302.9[MH+], Tr=6.98min.
Compound 1-118:[2-(3-1-yl)-6-((R)-2-methoxymethyl tetramethyleneimine-1-yl) pyrimidine-4-yl]-urethanum
At 0 ℃, (0.25mmol, (0.25mmol, 1eq.) (0.25mmol is 1eq.) in the 1ml exsiccant dichloromethane solution of dry pyridine for compound 1-96 and 0.02mL 1eq.) to add 75mg with the 75mg triphosgene.After 30 minutes, add exsiccant ethanol, at room temperature stir this solution then and spend the night.After reaction was finished, evaporating solvent was dissolved in 1mL methyl alcohol with residuum, then by the HPLC purifying.LCMS (method 1) m/z 375.1[MH+], Tr=5.93min.
By making compound 1-96 and suitable amine or the compound of pure prepared in reaction table 1C.
Table 1C
| Compound number | Reactant | ??R 3 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-118 | ??1-96 | Ethyl carbamate | ??374.4 | ??375.1 | ??5.9 | ??1 |
| ??1-119 | ??1-96 | The sec.-propyl urea | ??387.5 | ??388.1 | ??6.1 | ??1 |
| ??1-120 | ??1-96 | Dimethyl urea | ??373.5 | ??374.2 | ??4.9 | ??1 |
Compound 1-121:[2-(3-1-yl)-6-((R)-2-methoxymethyl tetramethyleneimine-1-yl) pyrimidine-4-yl] pyrazine-2-base amine
With nitrogen-burst agitation compound 1-96 (300mg, 1.0mmol, 1eq.), (+/-)-2,2 '-two (diphenylphosphine)-1,1 '-naphthyl naphthalene (187mg, 0.3mmol, 0.3eq.), acid chloride (II) (67mg, 0.3mmol, 0.3eq.), cesium carbonate (490mg, 1.5mmol, 1.5eq.) and the mixture 10min of toluene (10ml).(148mg, 1.3mmol 1.3eq.), stir this mixture then, and heat 21hr at 100 ℃ to add the 2-chloropyrazine.Add entry, use this mixture of ethyl acetate extraction then.Extraction liquid with dried over sodium sulfate merges filters, and concentrates then.Residuum is dissolved in 1: 1 methylene chloride of 50ml, filters the reject white solid then.Concentrated filtrate obtains yellow solid with chromatography (5% ethanol/methylene eluent) separation then on silica gel.Grind (1: 2 hexane s/ ethyl acetate) and obtain title compound (50mg), be pale solid.LCMS (method 1) m/z 381.0[MH+], Tr=5.80min.
By making compound 1-96 and suitable by substituent R
3The compound of the chlorine preparation table 1D of expression.
Table 1D
| Compound number | Reactant | ??R 3 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-121 | ??1-96 | The 2-pyrazine | ??380.4 | ??381.0 | ??5.8 | ??1 |
By making suitable above-mentioned intermediate and suitable by R
3The compound of the heterocycle prepared in reaction table 1E that the chlorine that substituting group is represented, bromine or iodine replace.
Table 1E
| Compound number | Intermediate | ??R 3 |
| ??1-206 | ??1-96 | Thiazol-2-yl |
| ??1-207 | ??1-96 | 3,6-dimethylpyrazine-2-base |
| ??1-208 | ??1-96 | Pyridine-2-base |
| ??1-209 | ??1-96 | 6-methoxyl group pyridazine-3-base |
| ??1-210 | ??1-96 | Pyrimidine-2-base |
| ??1-211 | ??1-96 | 3-cyanopyridine-2-base |
| ??1-212 | ??1-96 | 4,6-dimethyl pyrimidine-2-base |
| ??1-213 | ??1-96 | 6-picoline-2-base |
| ??1-214 | ??1-96 | 6-methyl pyridazine-3-base |
| ??1-215 | ??1-96 | 4-picoline-2-base |
| ??1-215 | ??1-96 | 5-cyanopyridine-2-base |
| ??1-217 | ??1-96 | 6-methoxypyridine-2-base |
| ??1-218 | ??1-96 | 4-cyanopyridine-2-base |
| ??1-219 | ??1-96 | 5-picoline-2-base |
| ??1-220 | ??1-96 | 3-cyanopyrazine-2-base |
| ??1-221 | ??1-96 | 5-fluorine pyridine-2-base |
| ??1-222 | ??1-96 | 5-cyanopyridine-2-base |
| ??1-223 | ??1-96 | 3-Methoxy Pyridine-2-base |
| ??1-224 | ??1-96 | 3-picoline-2-base |
| ??1-225 | ??1-96 | 1-methyl isophthalic acid H-imidazol-4 yl |
| Compound number | Intermediate | ??R 3 |
| ??1-226 | ??1-96 | 4-methoxypyridine-2-base |
| ??1-227 | ??1-96 | 1-methyl isophthalic acid H-imidazoles-2-base |
| ??1-228 | ??1-96 | 1,3,4-thiadiazoles-2-base |
| ??1-229 | ??1-96 | Thiazole-4-base |
| ??1-230 | ??1-96 | 1,4-dimethyl-1H-imidazoles-2-base |
Intermediate 15:N-(6-chloro-2-methylthiopyrimidine-4-yl)-O-methyl hydroxylamine
At 50 ℃, the sealing bottle in heat 1g (5.1mmol, 1eq) 4, (5.1mmol, 1eq.) (10.2mmol, 20mL dimethyl formamide solution 2eq.) spends the night for methoxy amine hydrochlorate and 1.8mL diisopropylamine for 6-two chloro-2-methylthiopyrimidines, 0.43g.Behind the evaporating solvent, the gradient with hexane and ethyl acetate (0-20%) on silica gel is that eluent obtains 0.7g (67% yield) product by liquid phase chromatography purifying residuum.LCMS (method 3) m/z 205.8[MH+], Tr=2.52min.
Intermediate 16:N-[6-chloro-2-(3-1-yl) pyrimidine-4-yl]-the O-methyl hydroxylamine
(2.4mmol, 1eq.) intermediate 15 is dissolved in THF/MeOH/ water (3/10/10) with 0.5g.Adding 2.9g (4.8mmol, 2eq.)
Stir this mixture then under the room temperature.After 3 hours, reaction finishes.Add entry (10mL) and ethyl acetate (50mL).Separate organic layer, use ethyl acetate (2x50mL) aqueous layer extracted then.Merge organic layer, use dried over mgso, evaporation obtains oily N-[6-chloro-2-(3-1-yl) pyrimidine-4-yl then]-the O-methyl hydroxylamine.It is dissolved in 5mL ethanol, adds 0.2mL (6.2mmol, 2.6eq.) anhydrous hydrazine then.Stir under the room temperature after 2 hours, and adding 0.3mL (3.0mmol, 1.2eq.) 2, the 4-diacetylmethane spends the night at 50 ℃ of these solution of heating then.After returning back to room temperature, evaporating solvent adds methylene dichloride (200mL), water (50mL) washing then.Use the dried over mgso organic layer, filter, concentrate then.Use 95: 5 methylene chloride on silica gel, to use this crude product of purified by flash chromatography as the eluent system.Obtain the intermediate 14 of 0.5g (40% yield), be yellow solid.LCMS (method 3) m/z 253.8[MH+], Tr=2.52min.
Compound 1-122:N-[2-(3-1-yl)-6-((R)-2-methoxymethyl tetramethyleneimine-1-yl) pyrimidine-4-yl]-the O-methyl hydroxylamine
At 80 ℃, in the bottle of sealing, heating 50mg (0.2mmol, 1eq.) (0.4mmol, 2eq.) spend the night for intermediate 16 and 50mg by the 1mL dioxane solution of (R)-2-methoxy ethyl tetramethyleneimine.After the cooling, evaporating solvent is dissolved in DCM with residuum, and the mixture with methylene dichloride/acetone (60/40) and 1% ammonium hydroxide passes through the PTLC purifying on silica gel then.LCMS (method 1) m/z332.9[MH+], Tr=4.92min.
Table 1F
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??1-122 | ??16 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??332.4 | ??332.9 | ??4.9 | ??1 |
Intermediate 17:2-furans carbonamidine (HCl)
With 2-cyano group furans (furonitrile) (5.0g, 53.2mmol, 1eq.) methyl alcohol (50mL) solution of adding sodium methylate (5.55mmol).Stirred this mixture 3 hours under the room temperature.(3.14g, 58.7mmol 1.1eq.), at room temperature stirred this mixture 68 hours then slowly to add ammonium chloride to gained solution.Filter gained suspension, decompression removes down and desolvates then.With ether (3x25mL) washing gained solid, obtain 7.5g (96% yield) 2-furans carbonamidine (HCl).
δ(200MHz，DMSO-d
6)：6.88-6.86(m，1H)；7.89(d，J＝3.8Hz，1H)；8.19(s，1H)；9.22(s，3H)。
Intermediate 18:2-(2-furyl) pyrimidine-4, the 6-glycol
(5.6g, 38.2mmol 1eq.) slowly add to ethanol (90mL) solution of sodium ethylate (0.191mol) with furans carbonamidine HCl 17.Stirred this mixture under the room temperature 30 minutes, add then diethyl malonate (4.87g, 30.4mmol, 0.8eq.).This suspension 32 hours refluxes.Decompression removes down and desolvates, and residuum is suspended in the water (100mL), with 5N hydrochloric acid it is acidified to pH=6 then.The solid that filter to produce, then water (50mL), ethanol/ether (4: 1,25mL), ether (2x25mL) washing.Obtain 2-(2-furyl) pyrimidine-4,6-glycol (4.2g, 78%) is light yellow solid.
δ(300MHz，DMSO-d
6)：5.00(s，1H)；6.60-6.70(m，1H)；7.40(d，J＝3.4Hz，1H)；7.80(s，1H)。
Intermediate 19:4,6-two chloro-2-(2-furyl) pyrimidine
Backflow intermediate 18 (3.0g, 16.8mmol, 1eq.) and N, N-diisopropylethylamine (3.85g, 29.8mmol, phosphoryl chloride 1.8eq.) (17mL) suspension 3 hours.Decompression removes down and desolvates, and slowly adds methylene dichloride (50mL) and ice then.Water (2x25mL), saturated solution of sodium bicarbonate (2x25mL), salt water washing organic layer, dry then (Na
2SO
4).Decompression removes down and desolvates, and obtains 4, and 6-two chloro-2-(2-furyl) pyrimidine (3.15g, 87%) is gray solid.
δ(300MHz，CDCl
3)：6.63-6.61(m，1H)；7.22(s，1H)；7.46(d，J＝3.4Hz，1H)；7.68(s，1H)。
Intermediate 20:6-chloro-2-(2-furyl) pyrimidine-4-amine
In voltage-resistant reactor, (2.0g, 9.3mmol) suspension in methyl alcohol (14mL) and 30% ammonium hydroxide (27mL) is 20 hours for heating intermediate 19.Remove partial solvent under the decompression.Filter the solid of gained, water (25mL), ether (25mL) washing, dry then.Obtain 6-chloro-2-(2-furyl) pyrimidine-4-amine (1.48g, 76%), be pale solid.
δ(400MHz，CDCl
3)：5.21(bs，2H)；6.31(s，1H)；6.54(m，1H)；7.28(d，J1＝3.7Hz，1H)；7.58(s，1H)。
Intermediate 21:6-chloro-2-(5-methyl furan-2-yl) pyrimidine-4-base amine
According to method described in the intermediate 20, be that raw material obtains title compound with 5-methyl-2-cyano group furans.
Intermediate 22:6-chloro-2-thiophene-2-yl pyrimidines-4-base amine
According to method described in the intermediate 20, be that raw material obtains title compound with thiophene-2-nitrile.
Intermediate 23:6-chloro-2-thiazol-2-yl pyrimidine-4-base amine
According to method described in the intermediate 20, be that raw material obtains title compound with thiazole-2-nitrile.
Intermediate 24:6-chloro-2-pyridine-2-yl pyrimidines-4-base amine
According to method described in the intermediate 20, be that raw material obtains title compound with the 2-cyanopyridine.
Intermediate 25:N-(6-chloro-2-furans-2-yl pyrimidines-4-yl) ethanamide
According to the method in the intermediate 5, obtain intermediate 25 by acylations intermediate 20.
Intermediate 26:N-[6-chloro-2-(5-methyl furan-2-yl) pyrimidine-4-yl] ethanamide
According to the method in the intermediate 5, obtain intermediate 26 by acylations intermediate 21.
Intermediate 27:N-(6-chloro-2-thiophene-2-yl pyrimidines-4-yl) ethanamide
According to the method in the intermediate 5, obtain intermediate 27 by acylations intermediate 22.
Intermediate 28:N-(6-chloro-2-thiazol-2-yl pyrimidine-4-yl) ethanamide
According to the method in the intermediate 5, obtain intermediate 28 by acylations intermediate 23.
Intermediate 29:N-(6-chloro-2-pyridine-2-yl pyrimidines-4-yl) ethanamide
According to the method in the intermediate 5, obtain intermediate 29 by acylations intermediate 24.
Intermediate 30:N-[6-chloro-2-(5-methyl furan-2-yl)-pyrimidine-4-yl]-2-(4-p-methoxy-phenyl) ethanamide
According to the method in the intermediate 11, replace chloroacetyl chloride with the p-methoxyphenyl Acetyl Chloride 98Min., obtain intermediate 30 by acylations intermediate 21.
By making suitable above-mentioned intermediate and suitable by substituent R
2The compound of the amine prepared in reaction table 2A of expression:
Table 2A
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??2-1 | ??25 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??316.4 | ??317.7 | ??7.7 | ??2 |
| ??2-2 | ??26 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??330.4 | ??331.4 | ??8.1 | ??2 |
| ??2-3 | ??26 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??330.4 | ??331.4 | ??8.1 | ??2 |
| ??2-4 | ??26 | (S)-2-methoxymethyl tetramethyleneimine-1-base | ??316.4 | ??317.1 | ??6.5 | ??2 |
| ??2-5 | ??26 | Two-(2-methoxy ethyl) amino | ??348.4 | ??349.4 | ??7.5 | ??2 |
| ??2-6 | ??26 | Methyl-(3-phenyl butyl) amino | ??380.4 | ??380.8 | ??8.2 | ??2 |
| ??2-7 | ??26 | Piperidines-1-base | ??300.4 | ??301.1 | ??8.6 | ??2 |
| ??2-8 | ??26 | (2-hydroxyethyl) methylamino | ??290.3 | ??290.8 | ??5.8 | ??2 |
| ??2-9 | ??26 | Ethylpyridine-4-ylmethyl amino | ??351.4 | ??351.9 | ??7.3 | ??2 |
| ??2-10 | ??26 | Lupetidine-1-base | ??328.4 | ??329.1 | ??9.8 | ??2 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??2-11 | ??26 | [1,3] dioxolane-2-ylmethyl methylamino | ??332.4 | ??333.2 | ??7.1 | ??2 |
| ??2-12 | ??26 | Dimethylamino | ??260.3 | ??260.9 | ??7.2 | ??2 |
| ??2-13 | ??26 | Azetidine-1-base | ??272.3 | ??273.1 | ??6.8 | ??2 |
| ??2-14 | ??26 | 2-propyl pyrrole alkane-1-base | ??328.4 | ??329.4 | ??9.9 | ??2 |
| ??2-15 | ??30 | Dimethylamino | ??366.4 | ??367.0 | ??5.7 | ??1 |
| ??2-16 | ??26 | 3-hydroxy piperidine-1-base | ??316.4 | ??316.5 | ??6.2 | ??2 |
| ??2-17 | ??26 | 4-methoxy methyl phenylpiperidines-1-base | ??344.4 | ??345.3 | ??8.2 | ??2 |
| ??2-18 | ??26 | (S)-2-methoxymethyl tetramethyleneimine-1-base | ??330.4 | ??331.3 | ??8.1 | ??2 |
| ??2-19 | ??26 | Morpholine-4-base | ??302.3 | ??302.9 | ??6.8 | ??2 |
| ??2-20 | ??21 | (S)-2-hydroxymethyl-pyrrolidine-1-base | ??274.3 | ??275.1 | ??5.9 | ??2 |
| ??2-21 | ??21 | (S)-2-methoxymethyl tetramethyleneimine-1-base | ??288.3 | ??288.8 | ??7.4 | ??2 |
| ??2-22 | ??26 | (S)-3-dimethylamino tetramethyleneimine-1-base | ??329.4 | ??329.5 | ??6.5 | ??2 |
| ??2-23 | ??26 | 2-ethoxyl methyl tetramethyleneimine-1-base | ??344.4 | ??344.7 | ??8.6 | ??2 |
| ??2-24 | ??26 | 4-methoxyl group piperidines-1-base | ??330.4 | ??330.9 | ??7.5 | ??2 |
| ??2-25 | ??28 | (S)-2-methoxymethyl tetramethyleneimine-1-base | ??333.4 | ??334.0 | ??4.6 | ??1 |
| ??2-26 | ??28 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??333.4 | ??334.0 | ??4.6 | ??1 |
| ??2-27 | ??27 | (S)-2-methoxymethyl tetramethyleneimine-1-base | ??332.4 | ??333.5 | ??8.8 | ??1 |
| Compound number | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??2-28 | ??29 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??327.4 | ??327.7 | ??6.7 | ??1 |
| ??2-29 | ??27 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??332.4 | ??332.9 | ??8.7 | ??1 |
| ??2-30 | ??29 | (S)-2-methoxymethyl tetramethyleneimine-1-base | ??327.4 | ??328.1 | ??6.7 | ??1 |
| ??2-31 | ??29 | Methoxyl group amino | ??259.3 | ??260.1 | ??5.1 | ??1 |
By making suitable above-mentioned intermediate and suitable by R
2The compound of the amine prepared in reaction table 2B of expression
Table 2B
Intermediate 31:6-chloro-2-(3-1-yl) pyrimidine-4-base amine
In dioxane (150mL), reflux 6-amino-2, the 4-dichloro pyrimidine (25.0g, 164mmol, 1eq.), pyrazoles (15.5g, 228mmol, 1.5eq.) and cesium carbonate (16.4g, 228mmol, 1.5eq.) 3 days.Reaction is cooled to room temperature, through diatomite filtration.With dioxane (300mL) washing diatomite, vacuum concentrated filtrate then.This residuum is suspended (slurried) in methylene dichloride 16 hours, filter then and obtain 8.1g intermediate 24, be pale solid.Repeat this operation with mother liquor and obtain another batch of product (3.6g) (39% total recovery).LCMS (method 3) m/z 196.0[MH+], Tr=1.99min.
Intermediate 32:N-(6-chloro-2-pyrazol-1-yl pyrimidine-4-yl) ethanamide
According to method described in the intermediate 5, acylations intermediate 31 obtains intermediate 32 with similar yield.LCMS (method 3) m/z 238.2[MH+], Tr=2.28min.
Intermediate 33:N-[6-chloro-2-(pyrazol-1-yl) pyrimidine-4-yl]-3-methylbutyryl amine
According to the similar methods that is used for intermediate 10, intermediate 31 and isobutyryl chloride are reacted prepare intermediate 33.Ethyl acetate/hexane mixture with 1/1 by liquid phase chromatography purifying residuum, obtains white solid with similar yield.LCMS (method 3) m/z 280.0[MH+], Tr=2.69min.
Intermediate 34:2-chloro-N-[6-chloro-2-(pyrazol-1-yl) pyrimidine-4-yl] ethanamide
According to the similar methods that is used for intermediate 11, intermediate 31 and chloroacetyl chloride are reacted prepare intermediate 34.
Intermediate 35:N-[6-chloro-2-(pyrazol-1-yl) pyrimidine-4-yl]-2-(4-methylpiperazine-1-yl) ethanamide
According to the similar methods that is used for intermediate 12, intermediate 34 and N-methyl piperidine are reacted prepare intermediate 35.
By making suitable above-mentioned intermediate and suitable by substituent R
2The compound of the amine prepared in reaction table 3 of expression:
Table 3
| Compound number. | Intermediate | ??R 2 | ??MW | The MS ion | Retention time (min) | The HPLC method |
| ??3-1 | ??33 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??358.4 | ??359. ??2 | ??0.8 | ??1 |
| ??3-2 | ??33 | 3,5-lupetidine-1-base | ??356.5 | ??357.2 | ??0.9 | ??1 |
| ??3-3 | ??32 | (R)-2-methoxymethyl tetramethyleneimine-1-base | ??316.4 | ??317.4 | ??6.7 | ??1 |
| ??3-4 | ??33 | 3,4-dihydro-1H-isoquinoline 99.9-2-base | ??376.5 | ??377.1 | ??1.0 | ??1 |
| ??3-5 | ??35 | 6-morpholine-4-base | ??386.5 | ??387.9 | ??5.8 | ??2 |
Though should be understood that for explanation and described specific embodiments of the present invention, under the situation that does not deviate from spirit and scope of the invention, can carry out various changes.Therefore, the present invention is except that being subjected to additional claim restriction, and is unrestricted.
Claims (22)
1. the compound of formula (I)
Or its pharmacologically acceptable salts, ester, solvate or steric isomer,
Wherein:
R
1It is the heterocycle that is randomly replaced by one or more members that are selected from low alkyl group, lower alkoxy, halogen and cyano group;
R
2Be NR
4R
5Or heterocycle, wherein said heterocycle is by 0-4 R
4Group replaces;
R
3Be H, R
6, OR
6, COR
6, CONR
6R
7, COOR
6Or containing the heteroaryl of at least one nitrogen, wherein said heteroaryl is randomly by 0-4 R
4Replace;
R
4Be selected from when occurring at every turn low alkyl group, lower alkoxy, alkoxyalkyl, oxo, cyano group, halogen, hydroxyl ,-C (O)-alkyl, low-grade alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycle and Heterocyclylalkyl, wherein said low alkyl group, lower alkoxy, alkoxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycle and heterocycloalkyl randomly by one or more low alkyl groups, halogen, lower alkoxy, hydroxyl, cyano group, aryl and-C (O)-alkyl replaces;
R
5Be selected from hydrogen, low alkyl group, lower alkoxy and alkoxyalkyl when occurring at every turn;
R
6Be low alkyl group, aralkyl, heteroaryl or Heterocyclylalkyl, wherein said low alkyl group, aralkyl, heteroaryl and heterocycloalkyl are randomly replaced by one or more members that are selected from low alkyl group, lower alkoxy, hydroxyl, oxo, halogen, amino, alkylamino and dialkyl amido; And
R
7Be hydrogen or low alkyl group, wherein said low-grade alkyl group is randomly replaced by one or more members that are selected from alkoxyl group, hydroxyl, oxo, halogen, amino, alkylamino and dialkyl amido.
2. the compound of claim 1, wherein R
1Be selected from pyrazolyl, triazolyl, furyl, thiazolyl and pyridyl, wherein said pyrazolyl, triazolyl, furyl, thiazolyl and pyridyl group are randomly replaced by one or more members that are selected from low alkyl group and halogen.
3. the compound of claim 2, wherein R
1Be the pyrazolyl that is randomly replaced by two low-grade alkyl groups, or the furyl that is randomly replaced by a low-grade alkyl group.
4. the compound of claim 3, wherein R
1Be selected from pyrazol-1-yl, 3,5-dimethyl-pyrazol-1-yl, furans-2-base and 5-methyl-furans-2-base.
5. the compound of claim 4, wherein R
1Be 3,5-dimethyl-pyrazol-1-yl or 5-methyl furan-2-base.
6. the compound of claim 1, wherein R
2Be the heterocycle that is selected from pyrrolidyl, piperidyl, indyl, pseudoindoyl, tetrahydric quinoline group, lactone group and piperazinyl, wherein said pyrrolidyl, piperidyl, indyl, pseudoindoyl, tetrahydric quinoline group, lactone group, lactam group, tetrahydro pyridyl and piperazinyl group are randomly by 0-4 R
4Group replaces.
7. the compound of claim 1, wherein R
2Be the heterocycle that is selected from pyrrolidyl, piperidyl, indyl, pseudoindoyl, tetrahydric quinoline group, lactone group and piperazinyl, wherein said pyrrolidyl, piperidyl, indyl, pseudoindoyl, tetrahydric quinoline group, lactone group, lactam group, tetrahydro pyridyl and piperazinyl group are randomly by 0-2 R
4Group replaces.
8. the compound of claim 1, wherein R
2Be pyrrolidyl, piperidyl, indyl or pseudoindoyl, wherein said pyrrolidyl, piperidyl, indyl or pseudoindoyl are randomly by 0-2 R
4Group replaces.
9. the compound of claim 1, wherein R
2Be pyrrolidyl, piperidyl, indyl or pseudoindoyl, wherein said pyrrolidyl, piperidyl, indyl or pseudoindoyl are randomly by 1-2 R
4Group replaces.
10. the compound of claim 1, wherein R
3Be COR
6
11. the compound of claim 10, wherein R
6It is low alkyl group.
12. the compound of claim 11, wherein R
6Be methyl, ethyl or sec.-propyl.
13. the compound of claim 12, wherein R
6It is methyl.
14. pharmaceutical composition, it comprises compound and the pharmaceutically acceptable carrier or the thinner of claim 1.
15. pharmaceutical composition, it comprises compound and the pharmaceutically acceptable carrier or the thinner of claim 3.
16. pharmaceutical composition, it comprises compound and the pharmaceutically acceptable carrier or the thinner of claim 7.
17. pharmaceutical composition, it comprises compound and the pharmaceutically acceptable carrier or the thinner of claim 11.
18. pharmaceutical composition, it comprises compound and the pharmaceutically acceptable carrier or the thinner of claim 13.
Be easy to by antagonism A 19. be used for the treatment of to suffer from
2AThe method of the individuality of the illness that Adenosine Receptors improves, described method comprises the pharmaceutical composition to described individual administration claim 1.
20. the method for claim 19, wherein said illness are ischemic, supraventricular arrhythmia, acute renal failure, reperfusion injury of cardiac muscle, autoimmune disorder, inflammatory bowel disease, asthma, diabetes, obesity, Parkinson's disease, Huntington Chorea, dystonia or dyskinesia.
21. claim 20 method, wherein said illness are ischemic, supraventricular arrhythmia, Parkinson's disease, Huntington Chorea, dystonia or dyskinesia.
22. claim 21 method, wherein said illness is Parkinson's disease.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86851706P | 2006-12-04 | 2006-12-04 | |
| US60/868,517 | 2006-12-04 | ||
| PCT/US2007/086380 WO2008070661A1 (en) | 2006-12-04 | 2007-12-04 | Substituted pyrimidines as adenosine receptor antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101679371A true CN101679371A (en) | 2010-03-24 |
Family
ID=39272263
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200780050872A Pending CN101679371A (en) | 2006-12-04 | 2007-12-04 | Substituted pyrimidines as adenosine receptor antagonists |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20100234341A1 (en) |
| EP (1) | EP2121662A1 (en) |
| JP (1) | JP2010511727A (en) |
| CN (1) | CN101679371A (en) |
| WO (1) | WO2008070661A1 (en) |
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| CN102772800A (en) * | 2011-12-20 | 2012-11-14 | 同济大学 | Application of medicament of target adenosine receptor A2BAR in preparing medicament for preventing or treating autoimmune diseases |
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| CN104447708A (en) * | 2013-12-10 | 2015-03-25 | 苏州大学 | Aminopyrimidine heterocyclic compound having adenosine receptor antagonistic activity |
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-
2007
- 2007-12-04 CN CN200780050872A patent/CN101679371A/en active Pending
- 2007-12-04 EP EP07865169A patent/EP2121662A1/en not_active Withdrawn
- 2007-12-04 WO PCT/US2007/086380 patent/WO2008070661A1/en active Application Filing
- 2007-12-04 US US12/517,546 patent/US20100234341A1/en not_active Abandoned
- 2007-12-04 JP JP2009540422A patent/JP2010511727A/en not_active Withdrawn
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| CN102772800A (en) * | 2011-12-20 | 2012-11-14 | 同济大学 | Application of medicament of target adenosine receptor A2BAR in preparing medicament for preventing or treating autoimmune diseases |
| CN103626741A (en) * | 2013-11-26 | 2014-03-12 | 苏州大学 | Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity |
| CN104447708A (en) * | 2013-12-10 | 2015-03-25 | 苏州大学 | Aminopyrimidine heterocyclic compound having adenosine receptor antagonistic activity |
| CN107286146A (en) * | 2017-07-05 | 2017-10-24 | 上海肇钰医药科技有限公司 | It is used as adenosine A2A4 aminopyridine derivatives of receptor antagonist and application thereof |
| WO2019007140A1 (en) * | 2017-07-05 | 2019-01-10 | 上海肇钰医药科技有限公司 | 4-aminopyrimidine derivative used as adenosine a2a receptor antagonist and application thereof |
| CN107286146B (en) * | 2017-07-05 | 2020-07-31 | 上海肇钰医药科技有限公司 | 4-aminopyrimidine derivatives as adenosine A2A receptor antagonists and uses thereof |
| WO2021159993A1 (en) * | 2020-02-14 | 2021-08-19 | Pharmablock Sciences (Nanjing) , Inc. | Inhibitors of interleukin-1 receptor associated kinase (irak) /fms-like receptor tyrosine kinase (flt3), pharmaceutical products thereof, and methods thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US20100234341A1 (en) | 2010-09-16 |
| WO2008070661A1 (en) | 2008-06-12 |
| JP2010511727A (en) | 2010-04-15 |
| EP2121662A1 (en) | 2009-11-25 |
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